Triazole Compounds And Methods Of Making And Using The Same

ABSTRACT

The present invention provides triazole macrocyclic compounds useful as therapeutic agents. More particularly, these compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents.

RELATED APPLICATIONS

This application claims priority to and is a continuation of U.S. Ser.No. 13/972,732, filed Aug. 21, 2013, now allowed, which is acontinuation of U.S. Ser. No. 13/616,962, filed Sep. 14, 2012, nowabandoned, which is a continuation of U.S. Ser. No. 11/990,883, filedSep. 17, 2009, now U.S. Pat. No. 8,278,281, which is a national stageapplication, filed under 35 U.S.C. § 371 of International ApplicationNo. PCT/US2006/033645, filed Aug. 24, 2006, which claims the benefit ofand priority to U.S. Provisional Application No. 60/711,443, filed Aug.24, 2005, and U.S. Provisional Application No. 60/762,907, filed Jan.26, 2006, the contents of each of which are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates generally to the field of anti-infective,anti-proliferative, anti-inflammatory, and prokinetic agents. Moreparticularly, the invention relates to a family of triazole macrocycliccompounds that are useful as such agents.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the1940s, many new compounds have been discovered or specifically designedfor use as antibiotic agents. It was once believed that infectiousdiseases could be completely controlled or eradicated with the use ofsuch therapeutic agents. However, such beliefs have been shaken becausestrains of cells or microorganisms resistant to currently effectivetherapeutic agents continue to evolve. In fact, virtually everyantibiotic agent developed for clinical use has ultimately encounteredproblems with the emergence of resistant bacteria. For example,resistant strains of Gram-positive bacteria such asmethicillin-resistant staphylococci, penicillin-resistant streptococci,and vancomycin-resistant enterococci have developed. These resistantbacteria can cause serious and even fatal results for patients infectedwith such resistant bacteria. Bacteria that are resistant to macrolideantibiotics have emerged. Also, resistant strains of Gram-negativebacteria such as H. influenzae and M. catarrhalis have been identified.See, e.g., F. D. Lowry, “Antimicrobial Resistance: The Example ofStaphylococcus aureus,” J. Clin. Invest., vol. 111, no. 9, pp. 1265-1273(2003); and Gold, H. S. and Moellering, R. C., Jr., “Antimicrobial-DrugResistance,” N. Engl. J. Med., vol. 335, pp. 1445-53 (1996).

The problem of resistance is not limited to the area of anti-infectiveagents. Resistance has also been encountered with anti-proliferativeagents used in cancer chemotherapy. Therefore, the need exists for newanti-infective and anti-proliferative agents that are both effectiveagainst resistant bacteria and resistant strains of cancer cells.

Despite the problem of increasing antibiotic resistance, no new majorclasses of antibiotics have been developed for clinical use since theapproval in the United States in 2000 of the oxazolidinonering-containing antibiotic, linezolid, which is sold under the tradename Zyvox®. See, R. C. Moellering, Jr., “Linezolid: The FirstOxazolidinone Antimicrobial,” Annals of Internal Medicine, vol. 138, no.2, pp. 135-142 (2003). Linezolid was approved for use as ananti-bacterial agent active against Gram-positive organisms. However,linezolid-resistant strains of organisms are already being reported.See, Tsiodras et al., Lancet, vol. 358, p. 207 (2001); Gonzales et al,Lancet, vol 357, p. 1179 (2001); Zurenko et al., Proceedings Of The39^(th) Annual Interscience Conference On Antibacterial Agenrts AndChemotherapy (ICAAC), San Francisco, Calif., USA (Sep. 26-29, 1999).

Another class of antibiotics is the macrolides, so named for theircharacteristic 14 to 16-membered ring. The macrolides also often haveone or more 6-membered sugar-derived rings attached to the mainmacrolide ring. The first macrolide antibiotic to be developed waserythromycin, which was isolated from a soil sample from the Philippinesin 1952. Even though erythromycin has been one of the most widelyprescribed antibiotics, its disadvantages are relatively lowbioavailability, gastrointestinal side effects, and a limited spectrumof activity, Another macrolide is the compound, azithromycin, which isan azolide derivative of erythromycin incorporating a methyl-substitutednitrogen in the macrolide ring. Azithromycin is sold under the tradename Zithromax®. A more recently introduced macrolide is telithromycin,which is sold under the trade name Ketek®. Telithromycin is asemisynthetic macrolide in which a hydroxyl group of the macrolide ringhas been oxidized to a ketone group. See Yong-Ji Wu, Highlights ofSemi-synthetic Developments from Erythromycin A, Current Pharm. Design,vol. 6, pp. 181-223 (2000), and Yong-Ji Wu and Wei-uo Su, RecentDevelopments on Ketolides and Macrolides, Curr. Med. Chem., vol. 8, no.14, pp. 1727-1758 (2001).

In the search for new therapeutic agents, researchers have triedcombining or linking various portions of antibiotic molecules to createmultifunctional or hybrid compounds Other researches have tried makingmacrolide derivatives by adding further substituents to the largemacrolide ring or associated sugar rings. However, this approach formaking macrolide derivatives has also met with limited success.

Notwithstanding the foregoing, there is an ongoing need for newanti-infective and anti-proliferative agents. Furthermore, because manyanti-infective and anti-proliferative agents have utility asanti-inflammatory agents and prokinetic agents, there is also an ongoingneed for new compounds useful as anti-inflammatory and prokineticagents. The present invention provides compounds that meet these needs.

SUMMARY OF THE INVENTION

The invention provides compounds useful as anti-infective agents and/oranti-proliferative agents, for example, anti-biotic agents,anti-microbial agents, anti-bacterial agents, anti-fungal agents,anti-parasitic agents, anti-viral agents, and chemotherapeutic agents.The present invention also provides compounds useful asanti-inflammatory agents, and/or prokinetic (gastrointestinalmodulatory) agents. The present invention also provides pharmaceuticallyacceptable salts, esters, N-oxides, or prodrugs thereof.

The present invention provides compounds having the structure:

or a stereoisomer, pharmaceutically acceptable salt, ester, N-oxide, orprodrug thereof. In the formula, variables A, T, X, R¹, R², R³, R¹¹, andn can be selected from the respective groups of chemical moieties laterdefined in the detailed description. In addition, the invention providesmethods of synthesizing the foregoing compounds. Following synthesis, atherapeutically effective amount of one or more of the compounds can beformulated with a pharmaceutically acceptable carrier for administrationto a mammal, particularly humans, for use as an anti-cancer,anti-biotic, anti-microbial, anti-bacterial, anti-fungal, anti-parasiticor anti-viral agent, or to treat a proliferative disease, aninflammatory disease or a gastrointestinal motility disorder, or tosuppress disease states or conditions caused or mediated by nonsense ormissense mutations. Accordingly, the compounds or the formulations canbe administered, for example, via oral, parenteral, or topical routes,to provide an effective amount of the compound to the mammal.

The foregoing and other aspects and embodiments of the invention can bemore fully understood by reference to the following detailed descriptionand claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a family of compounds that can be used asanti-proliferative agents and/or anti-infective agents. The compoundscan be used without limitation, for example, as anti-cancer,anti-microbial, anti-bacterial, anti-fungal, anti-parasitic and/oranti-viral agents. Further, the present invention provides a family ofcompounds that can be used without limitation as anti-inflammatoryagents, for example, for use in treating chronic inflammatory airwaydiseases, and/or as prokinetic agents, for example, for use in treatinggastrointestinal motility disorders such as gastroesophageal refluxdisease, gastroparesis (diabetic and post surgical), irritable bowelsyndrome, and constipation. Further, the compounds can be used to treator prevent a disease state in a mammal caused or mediated by a nonsenseor missense mutation.

The compounds described herein can have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom canbe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, GCN double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and can be isolated as a mixture of isomers or as separateisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless specificstereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. All tautomers of shown or described compounds are alsoconsidered to be part of the present invention.

1. Definitions

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R³) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more R³moieties, then the group can optionally be substituted with one, two,three, four, five, or more R³ moieties, and R³ at each occurrence isselected independently from the definition of R³. Also, combinations ofsubstituents and/or variables are permissible, but only if suchcombinations result in stable compounds.

A chemical structure showing a dotted line representation for a chemicalbond indicates that the bond is optionally present. For example, adotted line drawn next to a solid single bond indicates that the bondcan be either a single bond or a double bond.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent can be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

In cases wherein there are nitrogens in the compounds of the presentinvention, these can be converted to N-oxides by treatment with anoxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford othercompounds of the present invention. Thus, all shown and claimednitrogens are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

As used herein, the term “anomeric carbon” means the acetal carbon of aglycoside.

As used herein, the term “glycoside” is a cyclic acetal.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified-number of carbon atoms. C₁₋₆ alkyl is intended to include C₁,C₂, C₃, C₄, C₅, and C₆ alkyl groups. C₁₋₈ alkyl is intended to includeC₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, andn-octyl.

As used herein, “alkenyl” is intended to include hydrocarbon chains ofeither straight or branched configuration and one or more unsaturatedcarbon-carbon bonds that can occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl is intended to include C₂,C₃, C₄, C₅, and C₆ alkenyl groups. C₂₋₈ alkenyl is intended to includeC₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkenyl groups.

As used herein, “alkynyl” is intended to include hydrocarbon chains ofeither straight or branched configuration and one or more triplecarbon-carbon bonds that can occur in any stable point along the chain,such as ethynyl and propynyl. C₂₋₆ alkynyl is intended to include C₂,C₃, C₄, C₅, and C₆ alkynyl groups. C₂₋₈ alkynyl is intended to includeC₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkynyl groups.

Furthermore, “alkyl”, “alkenyl”, and “alkynyl” are intended to includemoieties which are diradicals, i.e., having two points of attachment, anexample of which in the present invention is when D is selected fromthese chemical groups. A nonlimiting example of such an alkyl moietythat is a diradical is —CH₂CH₂—, i.e., a C₂ alkyl group that iscovalently bonded via each terminal carbon atom to the remainder of themolecule.

As used herein, the terms used to describe various carbon-containingmoieties, including, for example, “alkyl,” “alkenyl,” “alkynyl,”“phenyl,” and any variations thereof, are intended to include univalent,bivalent, or multivalent species. For example, “C₁₋₆ alkyl-R³” isintended to represent a univalent C₁₋₆ alkyl group substituted with a R³group, and “O—C₁₋₆ alkyl-R³” is intended to represent a bivalent C₁₋₆alkyl group, i.e., an “alkylene” group, substituted with an oxygen atomand a R³ group.

As used herein, “cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₈ cycloalkylis intended to include C₃, C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo. “Counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl; and pentachloroethyl.

As used herein, “alkoxy” refers to an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.C₁₋₆ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxygroups. C₁₋₈ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇,and C₈ alkoxy groups. Examples of alkoxy include, but are not limitedto, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.

As used herein, “alkylthio” refers to an alkyl group as defined abovewith the indicated number of carbon atoms attached through an sulfurbridge. C₁₋₆ alkylthio, is intended to include C₁, C₂, C₃, C₄, C₅, andC₆ alkylthio groups. C₁₋₈ alkylthio, is intended to include C₁, C₂, C₃,C₄, C₅, C₆, C₇, and C₈ alkylthio groups. As used herein, “carbocycle” or“carbocyclic ring” is intended to mean, unless otherwise specified, anystable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclicor tricyclic ring, any of which can be saturated, unsaturated (includingpartially and fully unsaturated), or aromatic, recognizing that ringswith certain numbers of members cannot be bicyclic or tricyclic, e.g., a3-membered ring can only be a monocyclic ring. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl,cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl,cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl,indanyl, adamantly, and tetrahydronaphthyl. As shown above, bridgedrings are also included in the definition of carbocycle (e.g.,[2.2.2]bicyclooctane). A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. Preferred bridges are one ortwo carbon atoms. It is noted that a bridge always converts a monocyclicring into a tricyclic ring. When a ring is bridged, the substituentsrecited for the ring can also be present on the bridge. Fused (e.g.,naphthyl and tetrahydronaphthyl) and spiro rings are also included.

As used herein, the term “heterocycle” means, unless otherwise stated, astable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclicor tricyclic ring (recognizing that rings with certain numbers ofmembers cannot be bicyclic or tricyclic, e.g., a 3-membered ring canonly be a monocyclic ring), which is saturated, unsaturated (includingpartially and fully unsaturated), or aromatic, and consists of carbonatoms and one or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen,and sulfur, and including any bicyclic or tricyclic group in which anyof the above-defined heterocyclic rings is fused to a second ring (e.g.,a benzene ring). The nitrogen and sulfur heteroatoms can optionally beoxidized (i.e., N→O and S(O)_(p), where p=1 or 2). When a nitrogen atomis included in the ring it is either N or NH, depending on whether ornot it is attached to a double bond in the ring (i.e., a hydrogen ispresent if needed to maintain the tri-valency of the nitrogen atom). Thenitrogen atom can be substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, as defined). The heterocyclic ring can beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. The heterocyclic rings described hereincan be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. A nitrogen in the heterocycle can optionally bequaternized. Bridged rings are also included in the definition ofheterocycle. A bridged ring occurs when one or more atoms (i.e., C, O,N, or S) link two non-adjacent carbon or nitrogen atoms. Preferredbridges include, but are not limited to, one carbon atom, two carbonatoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogengroup. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring can also be present on the bridge. Spiro and fused rings arealso included.

As used herein, the term “aromatic heterocycle” or “heteroaryl” isintended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-memberedmonocyclic or bicyclic aromatic ring (recognizing that rings withcertain numbers of members cannot be a bicyclic aromatic, e.g.; a5-membered ring can only be a monocyclic aromatic ring), which consistsof carbon atoms and one or more heteroatoms, e.g.; 1 or 1-2 or 1-3 or1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen,oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings,only one of the two rings needs to be aromatic (e.g.,2,3-dihydroindole), though both can be (e.g., quinoline). The secondring can also be fused or bridged as defined above for heterocycles. Thenitrogen atom can be substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, as defined). The nitrogen and sulfurheteroatoms can optionally be oxidized (i.e., N→O and S(O)_(p), wherep=1 or 2). In some compounds, the total number of S and O atoms in thearomatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, parnoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,USA, p. 1445 (1990).

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention can be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate derivatives ofalcohol and amine functional groups in the compounds of the presentinvention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, “treating” or “treatment” means the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting its development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

As used herein, “mammal” refers to human and non-human patients.

As used herein, the term “therapeutically effective amount” refers to acompound, or a combination of compounds, of the present inventionpresent in or on a recipient in an amount sufficient to elicitbiological activity, for example, anti-microbial activity, anti-fungalactivity, anti-viral activity, anti-parasitic activity, and/oranti-proliferative activity. The combination of compounds is preferablya synergistic combination. Synergy, as described, for example, by Chouand Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs whenthe effect of the compounds when administered in combination is greaterthan the additive effect of the compounds when administered alone as asingle agent. In general, a synergistic effect is most clearlydemonstrated at sub-optimal concentrations of the compounds. Synergy canbe in terms of lower cytotoxicity, increased anti-proliferative and/oranti-infective effect, or some other beneficial effect of thecombination compared with the individual components.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present invention also consistessentially of, or consist of, the recited components, and that theprocesses of the present invention also consist essentially of, orconsist of; the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions are immaterial so long as the invention remains operable.Moreover, two or more steps or actions can be conducted simultaneously.

2. Compounds of the Invention

The invention provides a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrugthereof,wherein

A is selected from (a) a C₁₋₆ alkyl group, (b) a C₂₋₆ alkenyl group, (c)a C₂₋₆ alkynyl group, (d) a C₃₋₁₂ saturated, unsaturated, or aromaticcarbocycle, (e) a 3-12 membered saturated, unsaturated, or aromaticheterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f)H, (g) —OH (h) —SH, (i) F, (j) Cl, (k) Br, (l) I, (m) —CF₃, (n) —CN, (o)—N₃ (p) —NO₂, (q) —NR(CR⁶R⁶)_(t)R⁹, (r) —OR⁹, (s) —S(CR⁶R⁶)_(t)R⁹, (t)—S(O)(CR⁶R⁶)_(t)R⁹, (u) —S(O)₂(CR⁶R⁶)_(t)R⁹ (v) —C(O)(CR⁶R⁶)_(t)R⁹, (w)—OC(O)(CR⁶R⁶)_(t)R⁹, (x) —OC(O)O(CR⁶R⁶)_(t)R⁹, (y) —SC(O)(CR⁶R⁶)_(t)R⁹,(z) —C(O)O(CR⁶R⁶)_(t)R⁹, (aa) —NR⁶C(O)(CR⁶R⁶)_(t)R⁹, (bb)—C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (cc) —C(═NR⁶)(CR⁶R⁶)_(t)R⁹, (dd)—C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁹, (ee) —C[═NNR⁶C(O)R⁶](CR⁶R⁶)_(t)R⁹, (ff)—NR⁶C(O)O(CR⁶R⁶)_(t)R⁹, (gg) —OC(O)NR⁶(CR⁶R⁶)_(t)R⁹, (hh)—NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (ii) —NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁹, (jj)—S(O)_(p)NR(CR⁶R⁶)_(t)R⁹, (kk) —NR⁶R⁶, (ll) —NR⁶(CR⁶R⁶)_(t)R⁹, (mm)—SR⁶, (nn) —S(O)R⁶, (oo) —S(O)₂R⁶, (pp) —NR⁶C(O)R⁶, (qq) —Si(R¹³)₃, and(rr) —C(═O)H;

wherein (a)-(e) optionally are substituted with one or more R⁴ groups;

T is a 14- or 15-membered macrolide connected via a macrocyclic ringcarbon atom;

X is selected from —OR¹⁵ and —SR¹⁵,

R¹ and R³ independently are selected from: (a) H, (b) a C₁₋₆ alkylgroup, (c) a C₂₋₆ alkenyl group, (d) a C₂₋₆ alkynyl group, (e) —C(O)R⁵,(f) —C(O)OR⁵, (g) —C(O)—NR⁴R⁴, (h) —C(S)R⁵, (i) —C(S)OR⁵, (j) —C(O)SR⁵,or (k) —C(S)—NR⁴R⁴;

alternatively R¹ and R³ are taken together with the oxygen to which R¹is attached, the nitrogen to which R³ is attached and the twointervening carbons to form a 5 or 6 membered ring, said ring beingoptionally substituted with one or more R⁵;

R² is hydrogen or —OR²;

R⁴, at each occurrence, independently is selected from:

-   -   (a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) a        C₂₋₆ alkynyl group, (e) a C₆₋₁₀ saturated, unsaturated, or        aromatic carbocycle, (f) a 3-12 membered saturated, unsaturated,        or aromatic heterocycle containing one or more heteroatoms        selected from nitrogen, oxygen, and sulfur, (g) —C(O)—C₁₋₆        alkyl, (h) —C(O)—C₂₋₆ alkenyl, (i) —C(O)—C₂₋₆ alkynyl, (j)        —C(O)—C₆₋₁₀ saturated, unsaturated, or aromatic carbocycle, (k)        —C(O)-3-12 membered saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from        nitrogen, oxygen, and sulfur, (l) —C(O)O—C₁₋₆ alkyl, (m)        —C(O)O—C₂₋₆ alkenyl, (n) —C(O)O—C₂₋₆ alkynyl,    -   (o) —C(O)O—C₆₋₁₀ saturated, unsaturated, or aromatic        carbocycle, p) —C(O)O-3-12 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur, and q) —C(O)NR⁶R⁶,        -   wherein any of (b)-(p) optionally is substituted with one or            more R⁵ groups,

alternatively, NR⁶R⁶ forms a 3-7 membered saturated, unsaturated ofaromatic ring including the nitrogen atom to which the R⁶ groups areattached, wherein said ring is optionally substituted at a positionother than the nitrogen atom to which the R⁶ groups are attached, withone or more substituents selected from O, S(O)_(p), N, and NR⁸; R⁵ isselected from:

-   -   (a) R⁷, (b) a C₁₋₈ alkyl group, (c) a C₂₋₈ alkenyl group, (d) a        C₂₋₈ alkynyl group, (e) a C₃₋₁₂ saturated, unsaturated, or        aromatic carbocycle, and (f) a 3-12 membered saturated,        unsaturated, or aromatic heterocycle containing one or more        heteroatoms selected from nitrogen, oxygen, and sulfur, or two        R⁵ groups, when present on the same carbon atom can be taken        together with the carbon atom to which they are attached to form        a spiro 3-6 membered carbocyclic ring or heterocyclic ring        containing one or more heteroatoms selected from nitrogen,        oxygen, and sulfur;    -   wherein any of (b)-(f) immediately above optionally is        substituted with one or more R⁷ groups;

R⁶, at each occurrence, independently is selected from:

-   -   (a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) a        C₂₋₆ alkynyl group, (e) a C₃₋₁₀ saturated, unsaturated, or        aromatic carbocycle, and (f) a 3-10 membered saturated,        unsaturated, or aromatic heterocycle containing one or more        heteroatoms selected from nitrogen, oxygen, and sulfur,        -   wherein any of (b)-(f) optionally is substituted with one or            more moieties selected from:            -   (aa) a carbonyl group, (bb) a formyl group, (cc) F, (dd)                Cl, (ee) Br, (ff) I, (gg) CN, (hh) NO₂, (ii) —OR⁸, (jj)                —S(O)_(p)R⁸, (kk) —C(O)R⁸, (ll) —C(O)OR⁸, (mm) —OC(O)R⁸,                (nn) —C(O)NR⁸R⁸, (oo) —OC(O)NR⁸R⁸, (pp) —C(═NR⁸)R⁸, (qq)                —C(R⁸)(R⁸)OR⁸, (rr) —C(R⁸)₂OC(O)R⁸, (ss)                —C(R⁸)(OR⁸)(CH₂)_(r)NR⁸R⁸, (tt) —NR⁸R⁸, (uu) —NR⁸OR⁸,                (vv) —NR⁸C(O)R⁸, (ww) —NR⁸C(O)OR⁸, (xx) —NR⁸C(O)NR⁸R⁸,                (yy) —NR⁸S(O)_(r)R⁸, (zz) —C(OR⁸)(OR⁸)R⁸, (ab)                —C(R⁸)₂NR⁸R⁸, (ac) ═NR⁸, (ad) —C(S)NR⁸R⁸, (ae)                —NR⁸C(S)R⁸, (af) —OC(S)NR⁸R⁸, (ag) —NR⁸C(S)OR⁸, (ah)                —NR⁸C(S)NR⁸R⁸, (ai) —SC(O)R⁸, (aj) a C₁₋₈ alkyl group,                (ak) a C₂₋₈ alkenyl group, (al) a C₂₋₈ alkynyl group,                (am) a C₁₋₈ alkoxy group, (an) a C₁₋₈ alkylthio group,                (ao) a C₁₋₈ acyl group, (ap) —CF₃, (aq) —SCF₃, (ar) a                C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle,                and (as) a 3-10 membered saturated, unsaturated, or                aromatic heterocycle containing one or more heteroatoms                selected from nitrogen, oxygen, and sulfur,

alternatively, NR⁶R⁶ forms a 3-10 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R⁶ groups areattached wherein said ring is optionally substituted at a position otherthan the nitrogen atom to which the R⁶ groups are bonded, with one ormore moieties selected from O, S(O)_(p), N, and NR⁸;

alternatively, CR⁶R⁶ forms a carbonyl group;

R⁷, at each occurrence, is selected from:

-   -   (a) H, (b) ═O, (c) ═S, (d) F, (e) Cl, (f) Br, (g) I, (h)        —CF₃, (i) —CN, (j) —N₃ (k) —NO₂, (l) —NR(CR⁶R⁶)_(t)R⁹, (m)        —OR⁹, (n) —S(O)_(p)C(R⁶R⁶)_(t)R⁹, (o) —C(O)(CR⁶R⁶)_(t)R⁹, (p)        —OC(O)(CR⁶R⁶)_(t)R⁹, (q) —SC(O)(CR⁶R⁶)_(t)R⁹, (r)        —C(O)O(CR⁶R⁶)_(t)R⁹, (s) —NR⁶C(O)(CR⁶R⁶)_(t)R⁹, (t)        —C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (u) —C(═NR⁶)(CR⁶R⁶)_(t)R⁹, (v)        —C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁹, (w) —C(═NNR⁶C(O)R⁶)(CR⁶R⁶)_(t)R⁹, (x)        —C(═NOR⁹)(CR⁶R⁶)_(t)R⁹, (y) —NR⁶C(O)O(CR⁶R⁶)_(t)R⁹, (z)        —OC(O)NR⁶(CR⁶R⁶)_(t)R⁹, (aa) —NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (bb)        —NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁹, (cc) —S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁹, (dd)        —NR⁶S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁹, (ee) —NR⁶R⁶, (ff) —NR⁶(CR⁶R⁶),        (gg) —OH, (hh) —NR⁶R⁶, (ii) —OCH₃, (jj) —S(O)_(p)R⁶, (kk)        —NC(O)R⁶, (ll) a C₁₋₆ alkyl group, (mm) a C₂₋₆ alkenyl group,        (nn) a C₂₋₆ alkynyl group, (oo) —C₃₋₁₀ saturated, unsaturated,        or aromatic carbocycle, and (pp) 3-10 membered saturated,        unsaturated, or aromatic heterocycle containing one or more        heteroatoms selected from nitrogen, oxygen, and sulfur,        -   wherein any of (ll)-(pp) optionally is substituted with one            or more

R⁹ groups;

alternatively, two R⁷ groups can form —O(CH₂)_(u)O—;

R⁸ is selected from:

-   -   (a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) a        C₂₋₆ alkynyl group, (e) a C₃₋₁₀ saturated, unsaturated, or        aromatic carbocycle, (f) a 3-10 membered saturated, unsaturated,        or aromatic heterocycle containing one or more heteroatoms        selected from nitrogen, oxygen; and sulfur, (g) —C(O)—C₁₋₆        alkyl, (h) —C(O)—C₁₋₆ alkenyl, (i) —C(O)—C₁₋₆ alkynyl, (j)        —C(O)—C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle,        and (k) —C(O)-3-10 membered saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from        nitrogen, oxygen, and sulfur,        -   wherein any of (c)-(k) optionally is substituted with one or            more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd)            Br, (ee) I, (ff) CN, (gg) NO₂, (hh) OH, (ii) NH₂, (jj)            NH(C₁₋₆ alkyl), (kk) N(C₁₋₆ alkyl)₂, (ll) a C₁₋₆ alkoxy            group, (mm) an aryl group, (nn) a substituted aryl group,            (oo) a heteroaryl group, (pp) a substituted heteroaryl            group, and qq) a C₁₋₆ alkyl group optionally substituted            with one or more moieties selected from an aryl group, a            substituted aryl group, a heteroaryl group, a substituted            heteroaryl group, F, Cl, Br, I, CN, NO₂, CF₃, SCF₃, and OH;

R⁹, at each occurrence, independently is selected from:

-   -   (a) R¹⁰, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) a        C₂₋₆ alkynyl group, e) a C₃₋₁₀ saturated, unsaturated, or        aromatic carbocycle, and f) a 3-10 membered saturated,        unsaturated, or aromatic heterocycle containing one or more        heteroatoms selected from nitrogen, oxygen, and sulfur,        -   wherein any of (b)-(f) optionally is substituted with one or            more R¹⁰ groups;

R¹⁰, at each occurrence, independently is selected from:

-   -   (a) H, (b) ═O, (c) F, (d) Cl, (e) Br, (f) I, (g) —CF₃, (h)        —CN, (i) —NO₂, (j) —NR⁶R⁶, (k) —OR⁶, (l) —S(O)_(p)R⁶, (m)        —C(O)R⁶, (n) —C(O)OR⁶, (o) —OC(O)R⁶, (p) NR⁶C(O)R⁶, (q)        —C(O)NR⁶R⁶, (r) —C(═NR⁶)R⁶, (s) —NR⁶C(O)NR⁶R⁶, (t)        —NR⁶S(O)_(p)R⁶, (u) —S(O)_(p)NR⁶R⁶, (v) —NR⁶S(O)_(p)NR⁶R⁶, (w) a        C₁₋₆ alkyl group, (x) a C₂₋₆ alkenyl group, (y) a C₂₋₆ alkynyl        group, (z) a C₃₋₁₀ saturated, unsaturated, or aromatic        carbocycle, and (aa) a 3-10 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur,        -   wherein any of (w)-(aa) optionally is substituted with one            or more moieties selected from R⁶, F, Cl, Br, I, CN, NO₂,            —OR⁶, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, a C₁₋₆ alkoxy            group, a C₁₋₆ alkylthio group, and a C₁₋₆ acyl group;

R¹¹ at each occurrence, independently is selected from:

-   -   (a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO₂, (h)        OR⁸, (i) —S(O)_(p)R⁸, (j) —C(O)R⁸, (k) —C(O)OR⁸, (l)        —OC(O)R⁸, (m) —C(O)NR⁸R⁸, (n) —OC(O)NR⁸R⁸, (o) —C(═NR⁸)R⁸, (p)        —C(R⁸)(R⁸)OR⁸, (q) —C(R⁸)₂OC(O)R⁸, (r)        (—C(R⁸)(OR⁸)(CH₂)_(r)NR⁸R⁸, (s) —NR⁸R⁸, (t) —NR⁸OR⁸, (u)        —NR⁸C(O)R⁸, (v) —NR⁸C(O)OR⁸, (w) —NR⁸C(O)NR⁸R⁸, (x)        —NR⁸S(O)_(p)R⁸, (y) —C(OR⁸)(OR⁸)R⁸, (z) —C(R⁸)₂NR⁸R⁸, (aa)        —C(S)NR⁸R⁸, (bb) —NR⁸C(S)R⁸, (cc) —OC(S)NR⁸R⁸, (dd) —NR⁸C(S)OR⁸,        (ee) —NR⁸C(S)NR⁸R⁸, (ff) —SC(O)R⁸, (gg) —N₃, (hh)        —Si(R¹³)₃, (ii) a C₁₋₈ alkyl group, (jj) a C₂₋₈ alkenyl group,        (kk) a C₂₋₈ alkynyl group, (ll) a C₃₋₁₀ saturated, unsaturated,        or aromatic carbocycle, and (mm) a 3-10 membered saturated,        unsaturated, or aromatic heterocycle containing one or more        heteroatoms selected from nitrogen, oxygen, and sulfur, wherein        (ii)-(mm) optionally are substituted with one or more R⁵ groups;

R¹² is selected from:

-   -   (a) H; (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) a        C₂₋₆ alkynyl group, (e) —C(O)R⁵, (f) —C(O)OR⁵, (g)        —C(O)—NR⁴R⁴R⁴R⁴, (h) —C(S)R⁵, (i) —C(S)OR⁵, (j) —C(O)SR⁵, (k)        —C(S)—NR⁴R⁴R⁴R⁴, (l) a C₃₋₁₀ saturated, unsaturated, or aromatic        carbocycle, or (m) a 3-10 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur, (n) a —(C₁₋₆ alkyl)-C₃₋₁₀        saturated, unsaturated, or aromatic carbocycle, or (o) a —(C₁₋₆        alkyl)-3-10 membered saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from        nitrogen, oxygen, and sulfur,        -   wherein (a)-(d) and (l)-(o) optionally are substituted with            one or more R⁵ groups;

each R¹³ is independently selected from (a) —C₁₋₆ alkyl and (b) —O—(C₁₋₆alkyl);

R¹⁴ at each occurrence is independently selected from:

-   -   (a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO₂, (h)        OR⁸, (i) —S(O)_(p)R⁸, (j) —C(O)R⁸, (k) —C(O)OR⁸, (l)        —OC(O)R⁸, (m) —C(O)NR⁸R⁸, (n) —OC(O)NR⁸R⁸, (o) —C(═NR⁸)R⁸, (p)        —C(R⁸)(R⁸)OR⁸, (q) —C(R⁸)₂OC(O)R⁸, (r)        —C(R⁸)(OR⁸)(CH₂)NR⁸R⁸, (s) —NR⁸R⁸, (t) —NR⁸OR⁸, (u)        —NR⁸C(O)R⁸, (v) —NR⁸C(O)OR⁸, (w) —NR⁸C(O)NR⁸R⁸, (x)        —NR⁸S(O)_(p)R⁸, (y) —C(OR⁸)(OR⁸)R⁸, (z) —C(R⁸)₂NR⁸R⁸, (aa)        —C(S)NR⁸R⁸, (bb) —NR⁸C(S)R⁸, (cc) —OC(S)NR⁸R⁸, (dd) —NR⁸C(S)OR⁸,        (ee) —NR⁸C(S)NR⁸R⁸, (ff) —SC(O)R⁸, (gg) —N₃, (hh)        —Si(R¹³)₃, (ii) a C₁₋₈ alkyl group, (jj) a C₂₋₈ alkenyl group,        (kk) a C₂₋₈ alkynyl group, (ll) a C₃₋₁₀ saturated, unsaturated,        or aromatic carbocycle, and (mm) a 3-10 membered saturated,        unsaturated, or aromatic heterocycle containing one or more        heteroatoms selected from nitrogen, oxygen, and sulfur, wherein        (ii)-(mm) optionally are substituted with one or more R⁵ groups;    -   alternatively two R¹⁴ groups are taken together to form (a)        ═O, (b) ═S, (c) ═NR⁸, (e) ═NOR;

R¹⁵ is selected from C₁₋₆ alkyl, optionally substituted with from 1 to13 fluorine atoms;

n at each occurrence is 0, 1, 2, 3, or 4;

p at each occurrence is 0, 1, or 2;

r at each occurrence is 0, 1, or 2;

t at each occurrence is 0, 1, or 2;

and u at each occurrence is 1, 2, 3, or 4.

In further embodiments of the present invention, n is 1 or 2.

In further embodiments of the present invention, n is 1.

In further embodiments of the present invention, R¹¹ is F.

In further embodiments of the present invention, n is 0.

In further embodiments of the present invention, X is —OR¹⁵.

In further embodiments of the present invention, X is —SR¹⁵. In furtherembodiments of the present invention, R¹⁵ is C₁₋₃ alkyl, optionallysubstituted with from 1 to 7 fluorines.

In further embodiments of the present invention, R¹⁵ is C₁₋₂ alkyl,optionally substituted with from 1 to 5 fluorines.

In further embodiments of the present invention, R¹⁵ is selected from—CH₃, —CH₂F, —CHF₂, and —CF₃.

In further embodiments of the present invention, R⁵ is —CH₃.

In further embodiments of the present invention, A is selected from (a)a C₁₋₆ alkyl group, (b) a C₂₋₆ alkenyl group; (c) a C₂₋₆ alkynyl group,(d) a C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, (e) a 3-12membered saturated, unsaturated, or aromatic heterocycle containing oneor more nitrogen, oxygen or sulfur atoms, (f) —CF₃, (g)—NR⁶(CR⁶R⁶)_(t)R⁹, (h) —OR⁹, (i) —S(CR⁶R⁶)_(t)R⁹, (j)—S(O)(CR⁶R⁶)_(t)R⁹, (k) —S(O)₂(CR⁶R⁶)_(t)R⁹ (l) —C(O)(CR⁶R⁶)_(t)R⁹, (m)—OC(O)(CR⁶R⁶)_(t)R⁹, (n) OC(O)O(CR⁶R⁶)_(t)R⁹, (o) —SC(O)(CR⁶R⁶)_(t)R⁹,(p) —C(O)O(CR⁶R⁶)_(t)R⁹, (q) —NR⁶C(O)(CR⁶R⁶)_(t)R⁹, (r)—C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (s) —C(═NR⁶)(CR⁶R⁶)_(t)R⁹, (t)—C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁹, (u) —C[═NNR⁶C(O)R⁶](CR⁶R⁶)_(t)R⁹, (v)—NR⁶C(O)O(CR⁶R⁶)_(t)R⁹, (w) —OC(O)NR⁵(CR⁶R⁶)_(t)R⁹, (x)—NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (y) —NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁹, (z)—S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁹, (aa) —NR⁶R⁶, (bb) —NR⁶(CR⁶R⁶)_(t)R⁹, (cc)—SR⁶, (dd) —S(O)R⁶, (ee) —S(O)₂R⁶, and (ff) —NR⁶C(O)R⁶; wherein (a)-(e)optionally are substituted with one or more R¹⁴ groups;

In further embodiments of the present invention, A is selected from (a)a C₁₋₆ alkyl group, (b) a C₂₋₆ alkenyl group, (c) a C₂₋₆ alkynyl group,(d) a C₃₋₁₂ saturated, unsaturated, or aromatic carbocycle, (e) a 3-12membered saturated, unsaturated, or aromatic heterocycle containing oneor more nitrogen, oxygen or sulfur atoms; wherein (a)-(e) optionally aresubstituted with one or more R¹⁴ groups.

In further embodiments of the present invention, A is selected (a)—NR⁶(CR⁶R⁶)_(t)R⁹, (b) —OR⁹, (c) —S(CR⁶R⁶)_(t)R⁹, (d)—S(O)(CR⁶R⁶)_(t)R⁹, (e) —S(O)(CR⁶R⁶)_(t)R⁹ (f) —C(O)(CR⁶R⁶)_(t)R⁹, (g)—OC(O)(CR⁶R⁶)_(t)R⁹, (h) —OC(O)O(CR⁶R⁶)_(t)R⁹, (i) —SC(O)(CR⁶R⁶)_(t)R⁹,(j) —C(O)O(CR⁶R⁶)_(t)R⁹, (k) —NR⁶C(O)(CR⁶R⁶)_(t)R⁹, (l)—C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (m) —C(NR⁶)(CR⁶R⁶)_(t)R⁹, (n)—C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁹, (o) —C[═NNR⁶C(O)R⁶](CR⁶R⁶)_(t)R⁹, (p)—NR⁶C(O)O(CR⁶R⁶)_(t)R⁹, (q) —OC(O)NR(CR⁶R⁶)_(t)R⁹, (r)—NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (s) —NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁹, (t)—S(O)_(p)NR⁶(CR⁶)_(t)R⁹, (u) —NR⁶R⁶, (v) —NR⁶(CR⁶R⁶)_(t)R⁹, (w) —SR⁶,(x) —S(O)R⁶, (y) —S(O)₂R⁶, and (z) —NR⁶C(O)R⁶.

In further embodiments of the present invention, A is a C₁₋₆ alkylgroup, optionally substituted with one or more R¹⁴ groups.

In further embodiments of the present invention, A is a C₂₋₆ alkenylgroup, optionally substituted with one or more R¹⁴ groups.

In further embodiments of the present invention, A is a C₂₋₆ alkynylgroup, optionally substituted with one or more R¹⁴ groups.

In further embodiments of the present invention, A is a C₃₋₁₂ saturated,unsaturated, or aromatic carbocycle, optionally are substituted with oneor more R¹⁴ groups.

In further embodiments of the present invention, A is a 3-12 memberedsaturated, unsaturated, or aromatic heterocycle containing one or morenitrogen, oxygen or sulfur atoms, optionally substituted with one ormore R¹⁴ groups.

In further embodiments of the present invention, A is H.

Iii further embodiments of the present invention, A is —OH.

In further embodiments of the present invention, A is —SH.

In further embodiments of the present invention, A is F.

In further embodiments of the present invention, A is Cl.

In further embodiments of the present invention, A is Br.

In further embodiments of the present invention, A is I.

In further embodiments of the present invention, A is —CF₃. In furtherembodiments of the present invention, A is —CN.

In further embodiments of the present invention, A is —N₃.

In further embodiments of the present invention, A is —NO₂.

In further embodiments of the present invention, A is —NR⁶(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is —OR⁹.

In further embodiments of the present invention, A is —S(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—S(O)(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—S(O)₂(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—C(O)(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—OC(O)(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—OC(O)O(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—SC(O)(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—C(O)O(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—NR⁶C(O)(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—C(O)NR⁶(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—C(═NR⁶)(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—C[═NNR⁶C(O)R⁶](CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—NR⁶C(O)O(CR⁶R⁶)_(t)R.

In further embodiments of the present invention, A is—OC(O)NR⁶(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is—S(O)_(p)NR⁶(CR⁶R⁶)_(t)R.

In further embodiments of the present invention, A is —NR⁶R⁶.

In further embodiments of the present invention, A is —NR⁶(CR⁶R⁶)_(t)R⁹.

In further embodiments of the present invention, A is —SR⁶,

In further embodiments of the present invention, A is —S(O)R⁶.

In further embodiments of the present invention, A is —S(O)₂R⁶.

In further embodiments of the present invention, A is —NR⁶C(O)R⁶.

In further embodiments of the present invention, A is —Si(R¹³)₃.

In further embodiments of the present invention, A is and —C(═O)_(H).

In further embodiments of the present invention, R is selected from —CH₃and —OCH₃.

In further embodiments of the present invention, R¹³ is —CH₃.

In further embodiments of the present invention, R¹³ is —OCH₃.

In further embodiments, the invention provides a compound having thestructure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrugthereof, wherein R¹, R², R³, R¹¹, R¹⁵, n A, and T, are as describedherein.

In further embodiments, the invention provides a compound having thestructure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrugthereof, wherein R¹, R², R³, R¹¹, R¹⁵, n, A, and T, are as describedherein.

In further embodiments, the invention provides a compound having thestructure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrugthereof, wherein R¹, R², R³, R¹¹, n A, and T, are as described herein.

In further embodiments of the present invention, T is

wherein:

-   -   M is selected from:        -   (a) —C((O)—, (b) —CH(—OR¹¹⁴)—, (c) —NR¹¹⁴R¹¹⁴—CH₂—, (d)            —CH₂—NR¹¹⁴—, (e) —CH(NR¹¹⁴R¹¹⁴)—, (f) —C(═NNR¹¹⁴R¹¹⁴)—, (g)            —NR¹¹⁴—C(O)—, (h) —C(O)NR¹¹⁴—, (i) —C(═NR¹¹⁴—, (j)            —CR¹¹⁵R¹¹⁵—, and (k) —C(═NOR¹²⁷)—;    -   R¹⁰⁰ is selected from (a) H, (b) F, (c) Cl, (d) Br, (e) —SR¹¹⁴,        and (f) C₁₋₆ alkyl, wherein (f) optionally is substituted with        one or more R¹¹⁵ groups;    -   R^(1′)1 is selected from:        -   (a) H, (b) Cl, (c) F, (d) Br, (e) I, (f) —NR¹¹⁴R¹¹⁴, (g)            NR¹¹⁴C(O)R¹¹⁴, (h) OR¹¹⁴, (i) —OC(O)R¹¹⁴, (j)            —OC(O)OR¹¹⁴, (k) —OC(O)NR¹¹⁴R¹¹⁴, (l) —O—C₁₋₆ alkyl, (m)            —OC(O)—C₁₋₆ alkyl, (n) —OC(O)O—C₁₋₆ alkyl, (o)            —OC(O)NR¹¹⁴—C₁₋₆ alkyl,    -   (p) C₁₋₆ alkyl, (q) C₁₋₆ alkenyl, and (r) C₁₋₆ alkynyl,        -   wherein any of (l)-(r) optionally is substituted with one or            more R¹¹⁵ groups;    -   R¹⁰² is H, (b) F, (c) Cl, (d) Br, (e) —SR¹¹⁴, (f) C₁₋₆ alkyl,        wherein (f) optionally is substituted with one or more R¹¹⁵        groups;    -   R¹⁰³ is selected from:        -   (a) H, (b) —OR¹¹⁴, (c) —C₁₋₆ alkyl-R¹¹⁵, (d)            —OC((O)R¹¹⁴, (e) —OC(O)—C₁₋₆ alkyl-R¹¹⁵, (f)            —OC(O)OR¹¹⁴, (g) —OC(O)O—C₁₋₆ alkyl-(h) —OC(O)NR¹¹⁴R¹¹⁴, (i)            —OC(O)NR¹¹⁴—C₁₋₆ alkyl-R¹¹⁵, and (j)

-   -   alternatively, R¹⁰² and R¹⁰³ taken together with the carbon to        which they are attached form (a) a carbonyl group or (b) a 3-7        membered saturated, unsaturated or aromatic carbocyclic or        heterocyclic ring which can optionally be substituted with one        or more R¹¹⁴ groups;    -   alternatively, R¹⁰¹ and R¹⁰³ taken together are a single bond        between the respective carbons to which these two groups are        attached thereby creating a double bond between the carbons to        which R¹⁰⁰ and R¹⁰² are attached;    -   alternatively, R¹⁰¹ and R¹⁰³ taken together with the carbons to        which they are attached form a 3-membered saturated, unsaturated        or aromatic carbocyclic or heterocyclic ring which can        optionally be substituted with one or more R¹¹⁴ groups;    -   R¹⁰⁴ is selected from:        -   (a) H, (b) R¹⁴, (c) —C(O)R¹¹⁴ (d) —C(O)OR¹¹⁴ (e)            —C(O)NR¹¹⁴R¹¹⁴, (f) —C₁₋₆ alkyl-K—R¹¹⁴, (g)            —C₂₋₆alkenyl-K—R¹¹⁴, and (h) —C₂₋₆ alkynyl-K—R¹¹⁴;    -   K is selected from:        -   (a) —C(O)—, (b) —C(O)O—, (c) —C(O)NR¹¹⁴, (d)            —C(═NR¹¹⁴)—, (e) —C(═NR¹¹⁴)O—, (f) —C(═NR¹¹⁴)NR¹¹⁴, (g)            —OC(O)—, (h) —OC(O)O—, (i) —OC(O)NR¹¹⁴—, (j)            —NR¹¹⁴C(O)—, (k) —NR¹¹⁴C(O)O—, (l) —NR¹¹⁴C(O)NR¹¹⁴—, (m)            —NR¹¹⁴C(NR¹¹⁴)NR¹¹⁴—, and (o) —S(O)_(p)—;

alternatively R¹⁰³ and R¹⁰⁴, taken together with the atoms to which theyare bonded, form:

wherein R¹³⁵ and R³⁶ are selected from (a) hydrogen, (b) C₁₋₆ alkyl, (c)C₂₋₆ alkenyl, (d) C₂₋₆ alkynyl, (d) C₃₋₁₄ saturated, unsaturated oraromatic carbocycle, (e) 3-14 membered saturated, unsaturated oraromatic heterocycle containing one or more oxygen, nitrogen, or sulfuratoms, (f) F, (g) Br; (h) I, (i) OH, (j) —N₃, wherein (b) through (e)are optionally substituted with one or more R¹¹⁷; or alternatively, R¹³⁵and R¹³⁶ are taken together to form ═O, ═S and ═NR¹¹⁴, ═NOR¹¹⁴, —NR¹¹⁴,and ═N—NR¹¹⁴,R¹¹⁴],

wherein V is selected from (a) —(C₄-alkyl)-, (b) —(C₄-alkenyl)-, (c) O,(d) S, and (e) NR¹¹⁴, wherein (a) and (b) are optionally furthersubstituted with one or more R¹¹⁷;

R¹⁰⁵ is selected from:

-   -   (a) R¹¹⁴, (b) —OR¹¹⁴, (c) —NR¹¹⁴R¹¹⁴, (d) —O—C₁₋₆        alkyl-R¹¹⁵, (e) —C(O)—R¹¹⁴, (f) —C(O)—C₁₋₆ alkyl-R¹¹⁵, (g)        —OC(O)—R¹¹⁴, (h) —OC(O)—C₁₋₆ alkyl-R¹¹⁵, (i) —OC(O)O—R¹¹⁴, (j)        —OC(Q)O—C₁₋₆ alkyl-R¹¹⁵, (k) —OC(O)NR¹¹⁴R¹¹⁴, (l)        —OC(O)NR¹¹⁴—C₁₋₆ alkyl-R¹¹⁵, (m) —C(O)—C₂₋₆ alkenyl-R¹¹⁵,        and (n) —C(O)—C₂₋₆ alkynyl-R¹¹⁵;

alternatively, R¹⁰⁴ and R¹⁰⁵, taken together with the atoms to whichthey are bonded, form

-   -   wherein        -   Q is CH or N, and R¹²⁶ is —OR¹¹⁴, NR¹¹⁴ or R¹¹⁴;

alternatively, R¹⁰⁴ and R¹⁰⁵, taken together with the atoms to whichthey are bonded, form:

-   -   wherein        -   i) R¹⁰¹ is as defined above;        -   ii) alternately, R¹⁰¹ and R¹⁰⁹ can be taken together with            the carbon to which they are attached to form a carbonyl            group;        -   iii) alternately, R¹⁰¹ and R¹⁰⁹ can be taken together to            form the group —O(CR¹¹⁶R¹¹⁶)_(u)O—;

alternatively, R¹⁰⁴ and R¹⁰⁵, taken together with the atoms to whichthey are bonded, form:

wherein in the preceding structure the dotted line indicates an optionaldouble bond

-   -   i) R¹³⁰ is —OH, ═C(O), or R¹¹⁴,    -   ii) R¹³¹ is —OH, ═C(O), or R¹¹⁴,    -   iii) alternately, R¹³⁰ and R¹³¹ together with the carbons to        which they are attached form a 3-7 membered saturated,        unsaturated or aromatic carbocyclic or heterocyclic ring which        can optionally be substituted with one or more R¹¹⁴ groups;    -   iv) alternatively, R¹³⁰ and the carbon to which it is attached        or R¹³¹ and the carbon to which it is attached are each        independently —C(═O)—,

alternatively, R¹⁰⁵, R¹³² and M, taken together with the atoms to whichthey are attached, form:

R¹⁰⁶ is selected from:

-   -   (a) —OR¹¹⁴, (b) —C₁₋₆ alkoxy-R¹¹⁵, (c) —C(O)R¹¹⁴, (d)        —OC(O)R¹¹⁴, (e) —OC(O)OR¹¹⁴, (f) —OC(O)NR¹¹⁴R¹¹⁴, and (g)        —NR¹¹⁴R¹¹⁴,

alternatively, R¹⁰⁵ and R¹⁰⁶ taken together with the atoms to which theyare attached form a 5-membered ring by attachment to each other througha chemical moiety selected from:

-   -   (a) —OC(R¹¹⁵)₂O—, (b) —OC(O)O—, (c) —OC(O)NR¹¹⁴—, (d)        —NR¹¹⁴C(O)O—, (e) —OC(O)NOR¹¹⁴—, (f) NOR¹¹⁴C(O)O—, (g)        OC(O)NNR¹¹⁴R¹¹⁴—, (h) —NNR¹¹⁴R¹¹⁴—C(O)O—, (i) —OC(O)C(R¹¹⁵), (j)        —C(R¹¹⁵)₂C(O)O—, (k) —OC(S)O, (l) —OC((S)NR¹¹⁴—, (in)        —NR¹¹⁴C(S)O—, (n) —OC(S)NOR¹¹⁴R¹¹⁴, (o) —NOR¹¹⁴—C(S)O—, (p)        —OC(S)NNR¹¹⁴R¹¹⁴—, (q) —NNR¹¹⁴R¹¹⁴—C(S)O—, (r) —OC(S)C(R¹¹⁵)₂—,        and (s) —C(R¹¹⁵)₂C(S)O—;

alternatively, R¹⁰⁵, R¹⁰⁶, and R¹³³ taken together with the atoms towhich they are attached form:

alternatively, M, R¹⁰⁵, and R¹⁰⁶ taken together with the atoms to whichthey are attached form;

-   -   wherein in the preceding structure the dotted line indicates an        optional double bond,

wherein J¹ and J² are selected from hydrogen, Cl, F, Br, I, OH, —C₁₋₆alkyl, and —O(C₁₋₆alkyl) or are taken together to form ═O, ═S and═NR¹¹⁴, ═NOR¹¹⁴, ═NR¹¹⁴, and ═N—NR¹¹⁴,R¹¹⁴;alternatively, M and R¹⁰⁴ taken together with the atoms to which theyare attached form:

wherein U is selected from (a) —(C₄-alkyl)- and (b) —(C₄-alkenyl)-,wherein (a) and (b) are optionally further substituted with one or moreR¹¹⁷;

alternatively, M and R¹⁰⁵ are taken together with the atoms to whichthey are attached to form:

R¹⁰⁷ is selected from

-   -   (a) H, (b) —C₁₋₄ alkyl, (a) —C₂₋₄ alkenyl, which can be further        substituted with C₁₋₁₂ alkyl or one or more halogens, (d) —C₂₋₄        alkynyl, which can be further substituted with C₁₋₁₂ alkyl or        one or more halogens, (e) aryl or heteroaryl, which can be        further substituted with C₁₋₁₂ alkyl or one or more        halogens, (f) —C(O)H, (g) —COOH, (h) —CN, (i) —COOR¹¹⁴, (i)        —C(O)NR¹¹⁴R¹¹⁴, (k) —C(O)R¹¹⁴, and (l) —C(O)SR¹¹⁴, wherein (b)        is further substituted with one or more substituents selected        from (aa) —OR¹¹⁴, (bb) halogen, (cc) —SR¹¹⁴, (dd) C₁₋₁₂ alkyl,        which can be further substituted with halogen, hydroxyl, C₁₋₆        alkoxy, or amino, (ee) —OR¹¹⁴, (ff) —SR¹¹⁴, (gg) NR¹¹⁴R¹¹⁴, (hh)        —CN, (ii) —NO₂, (jj) —NC(O)R¹¹⁴, (k) —COOR¹¹⁴, (ll) —N₃, (mm)        ═N—O—R¹¹⁴, (nn) ═NR¹¹⁴, (oo) ═N—NR¹¹⁴R¹¹⁴, (pp) ═N—NH—C(O)R¹¹⁴,        and (qq) ═N—NH—C(O)NR¹¹⁴R¹¹⁴;

alternatively R¹⁰⁶ and R¹⁰⁷ are taken together with the atom to whichthey are attached to form an epoxide, a carbonyl, an olefin, or asubstituted olefin, or a C₃-C₇ carbocyclic, carbonate, or carbamate,wherein the nitrogen of said carbamate can be further substituted with aC₁-C₆ alkyl;

R¹⁰⁸ is selected from:

-   -   (a) C₁₋₆ alkyl, (b) C₁₋₆ alkenyl, and (c) C₂₋₆ alkynyl,        -   wherein any of (a)-(c) optionally is substituted with one or            more R¹¹⁴ groups;    -   R¹¹¹ is selected from H and —C(O)R¹¹⁴;

R¹¹² is selected from H, OH, and OR¹¹⁴;

R¹¹³ is selected from:

-   -   (a) H, (b) R¹¹⁴, (c) —C₁₋₆ alkyl-K—R¹¹⁴, (d) —C₂₋₆        alkenyl-K—R¹¹⁴, and (e) —C₂₋₆ alkynyl-K—R¹¹⁴,        -   wherein any of (c)-(e) optionally is substituted with one or            more R¹¹⁵ groups;

R¹¹⁴, at each occurrence, independently is selected from:

-   -   (a) H, (b) C₁₋₆ alkyl, (c) C₂₋₆ alkenyl, (d) C₂₋₆ alkynyl, (e)        C₆₋₁₀ saturated, unsaturated, or aromatic carbocycle, (f) 3-12        membered saturated, unsaturated, or aromatic heterocycle        containing one or more heteroatoms selected from nitrogen,        oxygen, and sulfur, (g) —C(O)—C₁₋₆ alkyl, (h) —C(O)—C₂₋₆        alkenyl, (i) —C(O)—C₂₋₆ alkynyl, (j) —C(O)—C₆₋₁₀ saturated,        unsaturated, or aromatic carbocycle, (k) —C(O)-3-12 membered        saturated, unsaturated, or aromatic heterocycle containing one        or more heteroatoms selected from nitrogen, oxygen, and        sulfur, (l) —C(O)O—C₁₋₆ alkyl, (m) —C(O)O—C₂₋₆ alkenyl, (n)        —C(O)O—C₂₋₆ alkynyl, (o) —C(O)O—C₆₋₁₀ saturated, unsaturated, or        aromatic carbocycle, (p) —C(O)O-3-12 membered saturated,        unsaturated, or aromatic heterocycle containing one or more        heteroatoms selected from nitrogen, oxygen, and sulfur, (q)        —C(O)NR¹¹⁶R¹¹⁶, (r) —NR¹¹⁶CO—C2-6 alkyl, (s) —NR¹¹⁶CO—C₆₋₁₀        saturated, unsaturated, or aromatic carbocycle, and (t)        —NR¹¹⁶C(O)-3-12 membered saturated, unsaturated, or aromatic        heterocycle containing one or more heteroatoms selected from        nitrogen, oxygen, and sulfur        -   wherein any of (b)-(t) optionally is substituted with one or            more R¹⁵ groups, wherein one or more non-terminal carbon            moieties of any of (b)-(d) optionally is replaced with            oxygen, S(O)_(p), or —NR¹¹⁶.

alternatively, NR¹¹⁴R¹¹⁴ forms a 3-7 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R¹¹⁴ groups arebonded and optionally one or more moieties selected from O, S(O)_(p), N,and NR¹¹⁸;

R¹¹⁵ is selected from:

-   -   (a) R¹¹⁷, (b) C₁₋₈ alkyl, (c) C₂₋₈ alkenyl, (d) C₂₋₈        alkynyl, (e) C₃₋₁₂ saturated, unsaturated, or aromatic        carbocycle, (f) 3-12 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur,        -   wherein any of (b)-(f) optionally is substituted with one or            more R¹¹⁷ groups;

R¹¹⁶, at each occurrence, independently is selected from:

-   -   (a) H, (b) C₁₋₆ alkyl, (c) C₂₋₆ alkenyl, (d) C₂₋₆ alkynyl, (e)        C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (f)        3-10 membered saturated, unsaturated, or aromatic heterocycle        containing one or more heteroatoms selected from nitrogen,        oxygen, and sulfur,        -   wherein one or more non-terminal carbon moieties of any of            (b)-(d) optionally is replaced with oxygen, S(O)_(p), or            —NR¹¹⁴, wherein any of (b)-(f) optionally is substituted            with one or more moieties selected from:            -   (aa) carbonyl, (bb) formyl, (cc) F, (dd) Cl, (ee) Br,                (ff) I, (gg) CN, (hh) N₃, (ii) NO, (jj) OR¹¹⁸, (kk)                —S(O)_(p)R¹¹⁸, (ll) —C(O)R¹¹⁸, (mm) —C(O)OR¹¹⁸, (nn)                —OC(O)R¹¹⁸, (oo) —C(O)NR¹¹⁸R¹¹⁸, (pp) —OC(O)NR¹¹⁸R¹¹⁸,                (qq) —C(═NR¹¹⁸)R¹¹⁸, (r) —C(R¹¹⁸)(R¹¹⁸)OR¹¹⁸, (ss)                —C(R¹¹⁸)₂OC(O)R¹¹⁸, (tt)                —C(R¹¹⁸)(OR¹¹⁸)(CH₂)_(r)NR¹¹⁸R¹¹⁸, (uu) —NR¹¹⁸R¹¹⁸; (vv)                —NR¹¹⁸OR¹¹⁸, (ww) —NR¹¹⁸C(O)R¹¹⁸, (xx) —NR¹¹⁸C(O)OR¹¹⁸,                (yy) —NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸, (zz) —NR¹¹⁸S(O)_(r)R¹¹⁸, (ab)                —C(OR¹¹⁸)(OR¹¹⁸)R¹¹⁸, (ac) —C(R¹¹⁸)₂NR¹¹⁸R¹¹⁸, (ad)                ═NR¹¹⁸, (ae) —C(S)NR¹¹⁸R¹¹⁸, (af) —NR¹¹⁸C(S)R¹¹⁸, (ag)                —OC(S)NR¹¹⁸R¹¹⁸, (ah) —NR¹¹⁸C(S)OR¹¹⁸, (ai)                —NR¹¹⁸C(S)NR¹¹⁸R¹¹⁸, (aj) —SC(O)R¹¹⁸, (ak) C₁₋₈ alkyl,                (al) C₂₋₈ alkenyl, (am) C₂₋₈ alkynyl, (an) C₁₋₈ alkoxy,                (ao) C₁₋₈ alkylthio, (ap) C₁₋₈ acyl, (aq) saturated,                unsaturated, or aromatic C₃₋₁₀ carbocycle, and (ar)                saturated, unsaturated, or aromatic 3-10 membered                heterocycle containing one or more heteroatoms selected                from nitrogen, oxygen, and sulfur,

alternatively, NR¹¹⁶R¹¹⁶ forms a 3-10 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R¹¹⁶ groups areattached and optionally one or more moieties selected from O, S(O)_(p),N, and NR¹¹⁸;

alternatively, CR¹¹⁶R¹¹⁶ forms a carbonyl group;

R¹¹⁷, at each occurrence, is selected from:

-   -   (a) H, (b) ═O, (c) F, (d) Cl, (e) Br, (f) I, (g)        (CR¹¹⁶R¹¹⁶)_(r)CF₃, (h) (CR¹¹⁶R¹¹⁶)_(r)CN, (i)        (CR¹¹⁶R¹¹⁶)_(r)NO2, (j)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶(CR¹⁶R¹¹⁶)_(t)R¹¹⁹, (k)        (CR¹¹⁶R¹¹⁶)_(r)OR¹¹⁹, (l)        (CR¹¹⁶R¹¹⁶)_(r)S(O)_(p)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (m)        (CR¹¹⁶R¹¹⁶)_(r)C(O)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (n)        (CR¹¹⁶R¹¹⁶)_(r)OC(O)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (o)        (CR¹¹⁶R¹¹⁶)_(r)SC(O)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (p)        (CR¹¹⁶R¹¹⁶)_(r)C(O)O(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (q)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶C(O)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (r)        (CR¹¹⁶R¹¹⁶)_(r)C(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (s)        (CR¹¹⁶R¹¹⁶)_(r)C(═NR¹¹⁶)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (t)        (CR¹¹⁶R¹¹⁶)_(r)C(═NNR¹¹⁶R¹¹⁶)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (u)        (CR¹¹⁶R¹¹⁶)_(r)C(═NNR¹¹⁶C(O)R¹¹⁶)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (v)        (CR¹¹⁶R¹¹⁶)_(r)C(═NOR¹¹⁹)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (w)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶C(O)O(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (x)        (CR¹¹⁶R¹¹⁶)_(r)OC(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (y)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶C(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (z)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶S(O)_(p)(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (aa)        (CR¹¹⁶R¹¹⁶)_(r)S(O)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (bb)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶S(O)_(p)NR¹¹⁶(CR¹¹⁶R¹¹⁶)_(t)R¹¹⁹, (cc)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶R¹¹⁶, (dd) C₁₋₆ alkyl, (ee) C₂₋₆ alkenyl,        (ff) C₂₋₆ alkynyl, (gg) (CR¹¹⁶R¹¹⁶)_(r)—C₃₋₁₀ saturated,        unsaturated, or aromatic carbocycle, and (hh)        (CR¹¹⁶R¹¹⁶)_(r)-3-10 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur,        -   wherein any of (dd)-(hh) optionally is substituted with one            or more R¹¹⁹ groups;

alternatively, two R¹¹⁷ groups can form —O(CH₂)_(u)—;

R¹¹⁸ is selected from:

-   -   (a) H, (b) C₁₋₆ alkyl, (o) C₂₋₆ alkenyl, (d) C₂₋₆ alkynyl, (e)        C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, (f) 3-10        membered saturated, unsaturated, or aromatic heterocycle        containing one or more heteroatoms selected from nitrogen,        oxygen, and sulfur, (g) —C(O)—C₁₋₆ alkyl, (h) —C(O)—C₁₋₆        alkenyl, (g) —C(O)—C₁₋₆ alkynyl, (i) —C(O)—C₃₋₁₀ saturated,        unsaturated, or aromatic carbocycle, and (j) —C(O)-3-10 membered        saturated, unsaturated, or aromatic heterocycle containing one        or more heteroatoms selected from nitrogen, oxygen, and sulfur,        -   wherein any of (b)-(j) optionally is substituted with one or            more moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd)            Br, (ee) I, (ff) CN, (gg) NO₂, (hh) OH, (ii) NH₂; (jj)            NH(C₁₋₆ alky(l), (kk) N(C₁₋₆ alky(l)₂, (ll) C₁₋₆            alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl,            (pp) substituted heteroaryl, and (qq) C₁₋₆ alkyl, optionally            substituted with one or more moieties selected from aryl,            substituted aryl, heteroaryl, substituted heteroaryl, F, Cl,            Br, I, CN, NO₂, and OH;

R¹¹⁹ at each occurrence, independently is selected from:

-   -   (a) R¹²⁰, (b) C₁₋₆ alkyl, (c) C₂₋₆ alkenyl, (d) C₂₋₆        alkynyl, (e) C₃₋₁₀ saturated, unsaturated, or aromatic        carbocycle, and (f) 3-10 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur,        -   wherein any of (b)-(f) optionally is substituted with one or            more R¹¹⁹ groups;

R¹²⁰, at each occurrence, independently is selected from:

-   -   (a) H, (b) ═O, (c) F, (d) Cl, (e) Br, (f) I, (g)        (CR¹¹⁶R¹¹⁶)_(r)CF₃, (h) (CR¹¹⁶R¹¹⁶)_(r)CN, (i)        (CR¹¹⁶R¹¹⁶)_(r)NO₂, (j) (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶R¹¹⁶, (k)        (CR¹¹⁶R¹¹⁶)_(r)OR¹¹⁴, (l) (CR¹¹⁶R¹¹⁶)_(r)S(O)_(p)R¹¹⁶, (m)        (CR¹¹⁶R¹¹⁶)_(r)C(O)R¹¹⁶, (n) (CR¹¹⁶R¹¹⁶)_(r)C(O)OR¹¹⁶, (o)        (CR¹¹⁶R¹¹⁶)_(r)OC(O)R¹¹⁶, (p) (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶C(O)R¹¹⁶, (q)        (CR¹¹⁶R¹¹⁶)_(r)C(O)NR¹¹⁶R¹¹⁶, (r)        (CR¹¹⁶R¹¹⁶)_(r)C(NR¹¹⁶)R¹¹⁶, (s)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶C(O)NR¹¹⁶R¹¹⁶, (t)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶S(O)_(p)R¹¹⁶, (u)        (CR¹¹⁶R¹¹⁶)_(r)S(O)_(p)NR¹¹⁶R¹¹⁶, (v)        (CR¹¹⁶R¹¹⁶)_(r)NR¹¹⁶S(O)_(p)NR¹¹⁶R¹¹⁶, (w) C₁₋₆ alkyl, (x) C₂₋₆        alkenyl, (y) C₂₋₆ alkynyl, (z) (CR¹¹⁶R¹¹⁶)_(r)—C₃₋₁₀ saturated,        unsaturated, or aromatic carbocycle, and (aa)        (CR¹¹⁶R¹¹⁶)_(r)-3-10 membered saturated, unsaturated, or        aromatic heterocycle containing one or more heteroatoms selected        from nitrogen, oxygen, and sulfur,        -   wherein any of (w)-(aa) optionally is substituted with one            or more moieties selected from R¹¹⁶, F, Cl, Br, I, CN, NO₂,            —OR¹¹⁶, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, C₁₋₆ alkoxy,            C₁₋₆ alkylthio, and C₁₋₆ acyl;

R¹²¹, at each occurrence, independently is selected from:

-   -   (a) I, (b) —OR¹¹⁸, (c) —O—C₁₋₆ alkyl-OC(O)R¹¹¹, (d) —O—C₁₋₆        alkyl-OC(O)OR¹¹⁸, (e) —O—C₁₋₆ alkyl-OC(O)NR¹¹⁸R¹¹⁸, (f) —O—C₁₋₆        alkyl-C(O)NR¹¹⁸R¹¹⁸, (g) —O—C₁₋₆ alkyl-NR¹¹⁸C(O)R¹¹⁸, (h)        —O—C₁₋₆ alkyl-NR¹¹⁸C(O)OR¹¹⁸, (i) —O—C₁₋₆        alkyl-NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸, (j) —O—C₁₋₆        alkyl-NR¹¹⁸C(═N(H)NR¹¹⁸R¹¹⁸, (k) —O—C₁₋₆ alkyl-S(O)_(p)R¹¹⁸, (l)        —O—C₂₋₆ alkenyl-OC(O)R¹¹⁸, (m) —O—C₂₋₆ alkenyl-OC(O)OR¹¹⁸, (n)        —O—C₂₋₆ alkenyl-OC(O)NR¹¹⁸R¹¹⁸, (o) —O—C₂₋₆        alkenyl-C(O)NR¹¹⁸R¹¹⁸, (p) —C₂₋₆ alkenyl-NR¹¹⁸C(O)R¹¹⁸, (q)        —O—C₂₋₆ alkenyl-NR¹¹¹⁸C(O)OR¹¹⁸, (r) —O—C₂₋₆        alkenyl-NR¹¹⁸C(O)NR¹¹⁸R¹¹⁸, (s) —O—C₂₋₆        alkenyl-NR¹¹⁸C(═N(H)NR¹¹⁸CR¹¹⁸, (t) —O—C₂₋₆        alkenyl-S(O)_(p)R¹¹⁸, (u) —O—C₂₋₆ alkynyl-OC(O)R¹¹⁸, (v) —O—C₂₋₆        alkynyl-OC(O)OR¹¹⁸, (w) —O—C₂₋₆ alkynyl-OC(O)NR¹¹⁸R¹¹⁸, (x)        —O—C₂₋₆ alkynyl-C(O)NR¹¹⁸R¹¹⁸ (y) —O—C₂₋₆        alkynyl-NR¹¹⁸C(O)R¹¹⁸, (z) —O—C₂₋₆ alkynyl-NR¹¹⁸C(O)OR¹¹⁸, (aa)        —O—C₂₋₆ alkynyl-NR¹¹¹⁸C(O)NR¹¹⁸R¹¹⁸, (bb) —O—C₂₋₆        alkynyl-NR¹¹⁸C(═N(H)NR¹¹⁸R¹¹⁸, (cc) —O—C₂₋₆        alkynyl-S(O)_(p)R¹¹⁸; and (dd) —NR¹¹⁸R¹¹⁸;    -   alternatively, two R¹²¹ groups taken together form ═O, ═NOR¹¹⁸,        or ═NNR¹¹⁸R¹¹⁸;

R¹²² is R¹¹⁵;

R¹²³ is selected from:

-   -   (a) R¹¹⁶, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO₂, and (h)        —OR¹¹⁴; alternatively, R¹²² and R¹²³ taken together are        —O(CH₂)_(u)O—;

R²⁴, at each occurrence, independently is selected from:

-   -   (a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) —OR⁴, (h)        —NO, (i) —NR¹¹⁴R¹¹⁴, (j) C₁₋₆ alkyl, (k) C₁₋₆ acyl, and (l) C₁₋₆        alkoxy;

R¹²⁵ is selected from:

-   -   (a) C₁₋₆ alkyl, (b) C₂₋₆ alkenyl, (c) C₂₋₆ alkynyl, (d) C₁₋₆        acyl, (e) C₁₋₆ alkoxy, (f) C₁₋₆ alkylthio, (g) saturated,        unsaturated, or aromatic C₅₋₁₀ carbocycle, (h) saturated,        unsaturated, or aromatic 5-10 membered heterocycle containing        one or more heteroatoms selected from nitrogen, oxygen, and        sulfur, (i) —O—C₁₋₆ alkyl-saturated, unsaturated, or aromatic        5-10 membered heterocycle containing one or more heteroatoms        selected from nitrogen, oxygen, and sulfur, (j) —NR¹¹⁴—C₁₋₆        alkyl-saturated, unsaturated, or aromatic 5-10 membered        heterocycle containing one or more heteroatoms selected from        nitrogen, oxygen, and sulfur, (k) saturated, unsaturated, or        aromatic 10-membered bicyclic ring system optionally containing        one or more heteroatoms selected from nitrogen, oxygen, and        sulfur, (l) saturated, unsaturated, or aromatic 13-membered        tricyclic ring system optionally containing one or more        heteroatoms selected from nitrogen, oxygen, and sulfur, (m)        —OR¹¹⁴, (n) —NR¹¹⁴R¹¹⁴, (o) —S(O)_(p)R¹¹⁴, and (p) —R¹²⁴,        -   wherein any of (a)-(l) optionally is substituted with one or            more R¹¹⁵ groups;

alternatively, R¹²⁵ and one R¹²⁴ group, taken together with the atoms towhich they are bonded, form a 5-7 membered saturated or unsaturatedcarbocycle, optionally substituted with one or more R¹¹⁵ groups; or a5-7 membered saturated or unsaturated heterocycle containing one or moreatoms selected from nitrogen, oxygen, and sulfur, and optionallysubstituted with one or more R¹¹⁵ groups;

R¹²⁶ at each occurrence, independently is selected from:

-   -   (a) hydrogen, (b) an electron-withdrawing group, (c) aryl, (d)        substituted aryl, (e) heteroaryl, (f) substituted heteroaryl,        and (g) C₁₋₆ alkyl, optionally substituted with one or more R¹¹⁵        groups;

alternatively, any R¹²⁶ and any R¹²³, taken together with the atoms towhich they are bonded, form a 5-7 membered saturated or unsaturatedcarbocycle, optionally substituted with one or more R¹¹⁵ groups; or a5-7 membered saturated or unsaturated heterocycle containing one or moreatoms selected from nitrogen, oxygen, and sulfur, and optionallysubstituted with one or more R¹¹⁵ groups;

R¹⁰⁹ is H of F;

R¹²⁷ is R¹¹⁴, a monosaccharide or disaccharide (including amino sugarsand halo sugar(s), —(CH₂)_(n)—(O—CH₂CH₂—)_(m)—O(CH₂)_(p)CH₃ or—(CH₂)_(n)(O—CH₂CH₂—)_(m)—OH

R¹²⁸ is R¹¹⁴;

R¹²⁹ is R¹¹⁴;

R¹¹⁰ is R¹¹⁴.

-   -   Alternatively, R¹⁰⁹ and R¹¹⁰ taken together with the carbons to        which they are attached form:

-   -   Alternately, R¹²⁸ and R¹²⁹ together with the carbons to which        they are attached form a 3-6 membered saturated, unsaturated or        aromatic carbocyclic or heterocyclic ring which can optionally        be substituted with one or more R¹¹⁴ groups;    -   R¹³², R¹³³, and R¹³⁴ are each independently selected from (a)        H, (b) F, (c) Cl, (d) Br, (e) —OR¹¹⁴ (f) —SR¹¹⁴, (g) —NR¹¹⁴R¹¹⁴,        and (b) C₁₋₆ alkyl, wherein (h) optionally is substituted with        one or more R¹¹⁵ groups;    -   alternatively, R¹³² and R¹³³ are taken together to form a        carbon-carbon double;    -   alternatively, R¹³³ and R¹³⁴ are taken together to form ═O, ═S,        ═NOR¹¹⁴, NR¹¹⁴ and ═N—NR¹¹⁴,R¹¹⁴;    -   alternatively, R¹⁰⁵ and R¹³⁴ are taken together with the carbons        to which they are attached to form a 3-membered ring, said ring        optionally containing an oxygen or nitrogen atom, and said ring        being optionally substituted with one or more R¹¹⁴ groups;    -   alternatively when M is a carbon moiety, R¹³⁴ and M are taken        together to form a carbon-carbon double bond;    -   k, at each occurrence is 0, 1, or 2;    -   m, at each occurrence is 0, 1, 2, 3, 4, or 5;    -   n, at each occurrence is 1, 2, or 3.

In further embodiments of the present invention, T is selected from:

wherein M, R¹⁰⁰, R¹⁰¹, R¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, andR¹²⁰ are as described

above and where the dotted lines indicate optional double bonds.

In further embodiments of the present invention, T is selected from:

wherein M, R¹⁰⁰, R¹⁰¹, R¹⁰², R¹⁰⁴, R¹⁰⁹, R¹¹⁴, R¹²⁶ and R¹²⁷ are asdescribed above.

In further embodiments of the present invention, T is selected from:

-   -   wherein M, R¹, R², R¹⁰⁴, R¹¹⁴, R¹⁰⁹ and R¹²⁷ are as described        above.

In further embodiments of the present invention T is selected from T1through T33:

In the present invention, the macrolide, “T” is defined to includevarious 14- and 15-membered ring systems, which can contain one or moreheteroatoms. Also, as defined herein, the macrolide, “T” is connectedvia a macrocyclic ring carbon atom”, which means that the connection orbond is made to a carbon atom on the 14- or 15-membered ring of themacrolide moiety. The macrolide can include further substituents,including ring substituents. For example, the substituent designated asR¹⁰³ can in certain embodiments be a sugar moiety, e.g. a cladinosesugar, or the substituents such as R¹⁰⁴ and R¹⁰⁵ are taken together incertain embodiments to form a bridged bicyclic ring system with themacrolide ring, or the substituents R¹⁰⁵ and R¹⁰⁶, are taken together incertain embodiments to form a fused bicyclic ring system with themacrolide ring, or the substituents or components M, R¹⁰⁵, and R¹⁰⁶ aretaken together to form a fused tricyclic ring system with the macrolidering, etc. It is also recognized in the present invention that “T” isdepicted as being connected to a 6-membered ring, for example in certainembodiments a desosamine sugar ring.

As is seen from the foregoing; the macrolide component of the compoundsof the present invention can comprise a wide range of structures.Examples of such macrolide components and their syntheses are providedin the following documents, all of which are incorporated by referencein their entirety: PCT application No. WO 2005/118610, published Dec.15, 2005; to Rib-X Pharmaceuticals, Inc.; PCT application No. WO2005/085266, published Sep. 15, 2005, to Rib-X Pharmaceuticals, Inc.;PCT application No. WO 20051049632, published Jun. 2, 2005, to Rib-XPharmaceuticals, Inc.; PCT application No. WO 2005/042554, published May12, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO2004/078770, published Sep. 16, 2004, to Rib-X Pharmaceuticals, Inc.;PCT application No. WO 2004/029066, published Apr. 8, 2004, to Rib-XPharmaceuticals, Inc.; U.S. patent No.; U.S. Pat. No. 6,992,069, to Guet al., issued Jan. 31, 2006; U.S. Pat. No. 6,953,782, to Phan et al.,issued Oct. 11, 2005; U.S. Pat. No. 6,939,861, to Ashley et al., issuedSep. 6, 2005; U.S. Pat. No. 6,927,057, to Khosla et al., issued Aug. 9,2005; U.S. Pat. No. 6,794,366, to Chu et al., issued Sep. 21, 2004; U.S.Pat. No. 6,762,168, to Chu, issued Jul. 13, 2004; U.S. Pat. No.6,756,359, to Chu et al, issued Jun. 29, 2994; U.S. Pat. No. 6,750,205,to Ashley et al, issued Jun. 15, 2004; U.S. Pat. No. 6,740,642, toAngebra et al., issued May 25, 2004; U.S. Pat. No. 6,727,352, to Chenget al., issued Apr. 27, 2004; U.S. Patent Application Publication No. US2006/0154881, to Or et al., published Jul. 13, 2006; U.S. PatentApplication Publication No. US 2006/0142215, to Tang et al., publishedJun. 29, 2006; U.S. Patent Application Publication No. US 2006/0142214,to Or et al, published Jun. 29, 2006; U.S. Patent ApplicationPublication No. US 2006/0122128, to Or et al., published Jun. 8, 2006;U.S. Patent Application Publication No. US 2006/0069048, to Or et al.published Mar. 30, 2006; U.S. Patent Application Publication No. US2005/0272672, to Li et al., published Dec. 8, 2005; U.S. PatentApplication Publication No US 2005/0009764, to Burger et al, publishedJan. 13, 2005; PCT application No. WO 2006/067589, to Pfizer ProductsInc., published Jun. 29, 2006; PCT application No. WO 2004/096823, toChiron Corporation, published Nov. 11, 2004; PCT application No. WO2004/096822, to Chiron Corporation, published Nov. 11, 2004; PCTapplication No. WO 2004/080391, to Optimer Pharmaceuticals, Inc.,published Sep. 23, 2004; PCT application No. WO 2004/078771, to TaishoPharmaceutical Co., Ltd., published Sep. 16, 2004; PCT application no.WO 03/061671, to Kosan Biosciences, Inc. published Jul. 31, 2003; andEuropean Patent Document EP 1 256 587 B1, to the Kitasato Institute,granted Mar. 29, 2006.

The invention also provides a compound having the structurecorresponding to any one of the structures listed in Table 1, 1A or 1C,or a pharmaceutically acceptable salt, ester, N-oxide, or prodrugthereof.

The invention also provides a pharmaceutical composition that containsone or more of the compounds described above and a pharmaceuticallyacceptable carrier.

The invention also provides a method for treating or preventing adisease state in a mammal by administering to a mammal in need thereofan effective amount of one or more of the compounds described above.

The invention also provides a method of treating a microbial infectionin a mammal by administering to the mammal an effective amount of one ormore of the compounds described above.

The invention also provides a method of treating a fungal infection in amammal by administering to the mammal an effective amount of one or moreof the compounds described above.

The invention also provides a method of treating a parasitic disease ina mammal by administering to the mammal an effective amount of one ormore of the compounds described above.

The invention also provides a method of treating a proliferative diseasein a mammal by administering to the mammal an effective amount of one ormore of the compounds described above.

The invention also provides a method of treating a viral infection in amammal by administering to the mammal an effective amount of one or moreof the compounds described above.

The invention also provides a method of treating an inflammatory diseasein a mammal by administering to the mammal an effective amount of one ormore of the compounds described above.

The invention also provides a method of treating a gastrointestinalmotility disorder in a mammal by administering to the mammal aneffective amount of one or more of the compounds described above.

The invention also provides a method of treating or preventing a diseasestate in a mammal caused or mediated by a nonsense or missense mutationby administering to the mammal an effective amount of one or more of thecompounds described above to suppress expression of the nonsense ormissense mutation.

In the methods described herein, the compound or compounds areadministered orally, parentally, or topically.

The invention also provides a method of synthesizing the compoundsdescribed above.

The invention also provides a medical device containing one or more ofthe compounds described above. For example, the device is a stent.

3. Synthesis of the Compounds of the Invention

The invention provides methods for making the compounds of theinvention. The following schemes depict exemplary chemistries availablefor synthesizing the compounds of the invention.

Scheme 1 illustrates the synthesis of triazole compounds of type 5 and6. Erythromycin can be N-demethylated as described in the art (U.S. Pat.No. 3,725,385; Flymnn et al. (1954) J. AM. CHEM. SOC. 76: 3121; Ku etal. (1997) BIOORG. MED. CHEM. LETT. 7: 1203; Stenmnark et al. (2000) J.ORG. CHEM. 65: 3875) to afford secondary amine 1. Alkylation of 1 withelectrophiles of type 2 yields alkynes of type 3 containing an alkylchain of appropriate length, generally between one and about four carbonatoms between the nitrogen atom and the alkyne group. Cycloaddition ofazides of type 4 with alkynes 3 generates two regioisomeric triazoleproducts. The reaction can be thermally catalyzed, or a number ofcatalysts could be added to facilitate the reaction (such as, but notlimited to, copper (I) iodide: see Tomoe, C. W. et al. (2002) J. ORG.CHEM. 67: 3057). The major isomer (for steric reasons) is the “anti”isomer 5, a 1,4 disubstituted triazole. The minor component is the “syn”isomer 6, a 1,5 disubstituted triazole.

It is to be understood that other macrolide compounds such as, but notlimited to, azithromycin and clarithromycin, could be N-demethylated andserve as starting materials for the chemistry exemplified in Scheme 1.Target compounds derived from such alternate macrolide precursors are tobe considered within the scope of the present invention.

An alternate approach to derivatives of type 5 and 6 is illustrated byScheme 2. Acetylenic alcohols of type 14 can be treated with azides 4 toyield intermediate alcohol 15 (along with a minor amount of theregioisomeric triazole). Tosylation of 15 will provide tosylates 16which can serve as alkylating agents for macrolide amines of type 1 toafford targets 5 (and its isomer 6). It will be appreciated that othersulfonate derivatives or halides could be formed from intermediatealcohol 15, and these would be useful as electrophiles for thealkylation of macrolide amines such as 1 to afford compounds of theinvention.

Other starting materials for the synthesis of compounds of the presentinvention are readily synthesizable.

4. Characterization of Compounds of the Invention

Compounds designed, selected and/or optimized by methods describedabove, once produced, can be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysisusing such assays. As a result, it can be possible to rapidly screen themolecules described herein for activity, for example, as anti-cancer,anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also,it can be possible to assay how the compounds interact with a ribosomeor ribosomal subunit and/or are effective as modulators (for example,inhibitors) of protein synthesis using techniques known in the art.General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening,Marcel Dekker, and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto; those described below.

(l) Surface Binding Studies.

A variety of binding assays can be useful in screening new molecules fortheir binding activity. One approach includes surface plasmon resonance(SPR) that can be used to evaluate the binding properties of moleculesof interest with respect to a ribosome, ribosomal subunit or a fragmentthereof.

SPR methodologies measure the interaction between two or moremacromolecules in real-time through the generation of aquantum-mechanical surface plasmon. One device, (BIAcore Biosensor® fromPharmacia Biosensor, Piscataway, N.J.) provides a focused beam ofpolychromatic light to the interface between a gold film (provided as adisposable biosensor “chip”) and a buffer compartment that can beregulated by the user. A 100 nm thick “hydrogel” composed ofcarboxylated dextran that provides a matrix for the covalentimmobilization of analytes of interest is attached to the gold film.When the focused light interacts with the free electron cloud of thegold film, plasmon resonance is enhanced. The resulting reflected lightis spectrally depleted in wavelengths that optimally evolved theresonance. By separating the reflected polychromatic light into itscomponent wavelengths (by means of a prism), and determining thefrequencies that are depleted, the BIAcore establishes an opticalinterface which accurately reports the behavior of the generated surfaceplasmon resonance. When designed as above, the plasmon resonance (andthus the depletion spectrum) is sensitive to mass in the evanescentfield (which corresponds roughly to the thickness of the hydrogel). Ifone component of an interacting pair is immobilized to the hydrogel, andthe interacting partner is provided through the buffer compartment, theinteraction between the two components can be measured in real timebased on the accumulation of mass in the evanescent field and itscorresponding effects of the plasmon resonance as measured by thedepletion spectrum. This system permits rapid and sensitive real-timemeasurement of the molecular interactions without the need to labeleither component.

(2) Fluorescence Polarization.

Fluorescence polarization (FP) is a measurement technique that canreadily be applied to protein-protein, protein-ligand, or RNA-ligandinteractions in order to derive IC₅₀s and Kds of the associationreaction between two molecules. In this technique one of the moleculesof interest is conjugated with a fluorophore. This is generally thesmaller molecule in the system (in this case, the compound of interest).The sample mixture, containing both the ligand-probe conjugate and theribosome, ribosomal subunit or fragment thereof, is excited withvertically polarized light. Light is absorbed by the probe fluorophores,and re-emitted a short time later. The degree of polarization of theemitted light is measured. Polarization of the emitted light isdependent on several factors, but most importantly on viscosity of thesolution and on the apparent molecular weight of the fluorophore. Withproper controls, changes in the degree of polarization of the emittedlight depends only on changes in the apparent molecular weight of thefluorophore, which in-turn depends on whether the probe-ligand conjugateis free in solution, or is bound to a receptor. Binding assays based onFP have a number of important advantages, including the measurement ofIC₅₀s and Kds under true homogenous equilibrium conditions, speed ofanalysis and amenity to automation, and ability to screen in cloudysuspensions and colored solutions.

(3) Protein Synthesis.

It is contemplated that, in addition to characterization by theforegoing biochemical assays, the compound of interest can also becharacterized as a modulator (for example, an inhibitor of proteinsynthesis) of the functional activity of the ribosome or ribosomalsubunit.

Furthermore, more specific protein synthesis inhibition assays can beperformed by administering the compound to a whole organism, tissue,organ, organelle, cell, a cellular or subcellular extract, or a purifiedribosome preparation and observing its pharmacological and inhibitoryproperties by determining, for example, its inhibition constant (IC₅₀)for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵Smethionine, or similar experiments can be performed to investigateprotein synthesis-activity. A change in the amount or the rate ofprotein synthesis in the cell in the presence of a molecule of interestindicates that the molecule is a modulator of protein synthesis. Adecrease in the rate or the amount of protein synthesis indicates thatthe molecule is a inhibitor of protein synthesis.

Furthermore, the compounds can be assayed for anti-proliferative oranti-infective properties on a cellular level. For example, where thetarget organism is a microorganism, the activity of compounds ofinterest can be assayed by growing the microorganisms of interest inmedia either containing or lacking the compound. Growth inhibition canbe indicative that the molecule can be acting as a protein synthesisinhibitor. More specifically, the activity of the compounds of interestagainst bacterial pathogens can be demonstrated by the ability of thecompound to inhibit growth of defined strains of human pathogens. Forthis purpose, a panel of bacterial strains can be assembled to include avariety, of target pathogenic species, some containing resistancemechanisms that have been characterized. Use of such a panel oforganisms permits the determination of structure-activity relationshipsnot only in regards to potency and spectrum, but also with a view toobviating resistance mechanisms. The assays can be performed inmicrotiter trays according to conventional methodologies as published byThe National Committee for Clinical Laboratory Standards (NCCLS)guidelines (NCCLS. M7-A5-Methods for Dilution AntimicrobialSusceptibility Tests for Bacteria That Grow Aerobically; ApprovedStandard-Fifth Edition. NCCLS Document M100-S12/M7 (ISBN1-56238-394-9)).

5. Formulation and Administration

The compounds of the invention can be useful in the prevention ortreatment of a variety of human or other animal, including mammalian andnon mammalian, disorders, including for example, bacterial infection,fungal infections, viral infections, parasitic diseases, and cancer. Itis contemplated that, once identified, the active molecules of theinvention can be incorporated into any suitable carrier prior to use;The dose of active molecule, mode of administration and use of suitablecarrier will depend upon the intended recipient and target organism. Theformulations, both for veterinary and for human medical use, ofcompounds according to the present invention typically include suchcompounds in association with a pharmaceutically acceptable carrier.

The carrier(s) should be “acceptable” in the sense of being compatiblewith the other ingredients of the formulations and not deleterious tothe recipient. Pharmaceutically acceptable carriers, in this regard, areintended to include any and all solvents, dispersion media, coatings,anti-bacterial and anti-fungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances isknown in the art. Except insofar as any conventional media or agent isincompatible with the active compound, use thereof in the compositionsis contemplated. Supplementary active compounds (identified or designedaccording to the invention and/or known in the art) also can beincorporated into the compositions. The formulations can conveniently bepresented in dosage unit form and can be prepared by any of the methodswell known in the art of pharmacy/microbiology. In general, someformulations are prepared by bringing the compound into association witha liquid carrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention should be formulated to becompatible with its intended route of administration. Examples of routesof administration include oral or parenteral, for example, intravenous,intradermal, inhalation, transdermal (topical), transmucosal, and rectaladministration. Solutions or suspensions used for parenteral,intradermal, or subcutaneous application can include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose, pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

Useful solutions for oral or parenteral administration can be preparedby any of the methods well known in the pharmaceutical art, described,for example, in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.),Mack Pub., (1990), Formulations for parenteral administration can alsoinclude glycocholate for buccal administration, methoxysalicylate forrectal administration, or citric acid for vaginal administration. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Suppositories forrectal administration also can be prepared by mixing the drug with anon-irritating excipient such as cocoa butter, other glycerides, orother compositions which are solid at room temperature and liquid atbody temperatures. Formulations also can include, for example,polyalkylene glycols such as polyethylene glycol, oils of vegetableorigin, and hydrogenated naphthalenes. Formulations for directadministration can include glycerol and other compositions of highviscosity. Other potentially useful parenteral carriers for these drugsinclude ethylene-vinyl acetate copolymer particles, osmotic pumps,implantable infusion systems, and liposomes. Formulations for inhalationadministration can contain as excipients, for example, lactose, or canbe aqueous solutions containing, for example, polyoxyethylene-9-laurylether, glycocholate and deoxycholate, or oily solutions foradministration in the form of nasal drops, or as a gel to be appliedintranasally. Retention enemas also can be used for rectal delivery.

Formulations of the present invention suitable for oral administrationcan be in the form of: discrete units such as capsules, gelatincapsules, sachets, tablets, troches, or lozenges, each containing apredetermined amount of the drug; a powder or granular composition; asolution or a suspension in an aqueous liquid or non-aqueous liquid; oran oil-in-water emulsion or a water-in-oil emulsion. The drug can alsobe administered in the form of a bolus, electuary or paste. A tablet canbe made by compressing or moulding the drug optionally with one or moreaccessory ingredients. Compressed tablets can be prepared bycompressing, in a suitable machine, the drug in a free-flowing form suchas a powder or granules, optionally mixed by a binder, lubricant, inertdiluent, surface active or dispersing agent. Moulded tablets can be madeby moulding, in a suitable machine, a mixture of the powdered drug andsuitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients. Oral compositions preparedusing a fluid carrier for use as a mouthwash include the compound in thefluid carrier and are applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules; troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). Itshould be stable under the conditions of manufacture and storage andshould be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (for example,glycerol, propylene glycol, and liquid polyethylene glycol), andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. In many cases, it will be preferable to include isotonicagents, for example, sugars, polyalcohols such as manitol, sorbitol, orsodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfilter sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation include vacuumdrying and freeze-drying which yields a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in theform of a sterile aqueous preparation of the drug that can be inmicrocrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems can also be used to present the drug for bothintra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eyetreatment, include liquid or semi-liquid preparations such as liniments,lotions, gels, applicants, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes; or solutions or suspensions such asdrops. Formulations for topical administration to the skin surface canbe prepared by dispersing the drug with a dermatologically acceptablecarrier such as a lotion, cream, ointment or soap. Particularly usefulare carriers capable of forming a film or layer over the skin tolocalize application and inhibit removal. For topical administration tointernal tissue surfaces, the agent can be dispersed in a liquid tissueadhesive or other substance known to enhance adsorption to a tissuesurface. For example, hydroxypropylcellulose or fibrinogen/thrombinsolutions can be used to advantage. Alternatively, tissue-coatingsolutions, such as pectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling orspray formulations) dispensed with a spray can, a nebulizer, or anatomizer can be used. Such formulations can be in the form of a finepowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect can beachieved either by choice of a valve having the desired spraycharacteristics (i.e., being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. For administration byinhalation, the compounds also can be delivered in the form of anaerosol spray from pressured container or dispenser which contains asuitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants generally are known in the art, and include, forexample, for transmucosal administration, detergents and bile salts.Transmucosal administration can be accomplished through the use of nasalsprays or suppositories. For transdermal administration, the activecompounds typically are formulated into ointments, salves, gels, orcreams as generally known in the art.

The active compounds can be prepared with carriers that will protect thecompound against rapid elimination from the body, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Methods for preparation of suchformulations will be apparent to those skilled in the art. Liposomalsuspensions can also be used as pharmaceutically acceptable carriers.These can be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit formfor ease of administration and uniformity of dosage. Dosage unit formrefers to physically discrete units suited as unitary dosages for thesubject to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals. Furthermore, administration can be by periodicinjections of a bolus, or can be made more continuous by intravenous,intramuscular or intraperitoneal administration from an externalreservoir (e.g., an intravenous bag).

Where adhesion to a tissue surface is desired the composition caninclude the drug dispersed in a fibrinogen-thrombin composition or otherbioadhesive. The compound then can be painted, sprayed or otherwiseapplied to the desired tissue surface. Alternatively, the drugs can beformulated for parenteral or oral administration to humans or othermammals, for example, in therapeutically effective amounts, e.g.,amounts that provide appropriate concentrations of the drag to targettissue for a time sufficient to induce the desired effect.

Where the active compound is to be used as part of a transplantprocedure, it can be provided to the living tissue or organ to betransplanted prior to removal of tissue or organ from the donor. Thecompound can be provided to the donor host. Alternatively or, inaddition, once removed from the donor, the organ or living tissue can beplaced in a preservation solution containing the active compound. In allcases, the active compound can be administered directly to the desiredtissue, as by injection to the tissue, or it can be providedsystemically, either by oral or parenteral administration, using any ofthe methods and formulations described herein and/or known in the art.Where the drug comprises part of a tissue or organ preservationsolution, any commercially available preservation solution can be usedto advantage. For example, useful solutions known in the art includeCollins solution, Wisconsin solution, Belzer solution, Eurocollinssolution and lactated Ringer's solution.

The compounds of the present invention can be administered directly to atissue locus by applying the compound to a medical device that is placedin contact with the tissue. An example of a medical device is a stent,which contains or is coated with one or more of the compounds of thepresent invention,

For example, an active compound can be applied to a stent at the site ofvascular injury. Stents can be prepared by any of the methods well knownin the pharmaceutical art. See, e.g., Fattori, R. and Piva, T., “DrugEluting Stents in Vascular Intervention,” Lancet, 2003, 361, 247-249;Morice, M. C., “A New Era in the Treatment of Coronary Disease?”European Heart Journal, 2003, 24, 209-211; and Toutouzas, K. et al.,“Sirolimus-Eluting Stents: A Review of Experimental and ClinicalFindings,” Z. Kardiol., 2002, 91(3), 49-57. The stent can be fabricatedfrom stainless steel or another bio-compatible metal, or it can be madeof a bio-compatible polymer. The active compound can be linked to thestent surface, embedded and released from polymer materials coated onthe stent, or surrounded by and released through a carrier which coatsor spans the stent. The stent can be used to administer single ormultiple active compounds to tissues adjacent to the stent.

Active compound as identified or designed by the methods describedherein can be administered to individuals to treat disorders(prophylactically or therapeutically). In conjunction with suchtreatment, pharmacogenomics (i.e., the study of the relationship betweenan individual's genotype and that individual's response to a foreigncompound or drug) can be considered. Differences in metabolism oftherapeutics can lead to severe toxicity or therapeutic failure byaltering the relation between dose and blood concentration of thepharmacologically active drug. Thus, a physician or clinician canconsider applying knowledge obtained in relevant pharmacogenomicsstudies in determining whether to administer a drug as well as tailoringthe dosage and/or therapeutic regimen of treatment with the drug.

In therapeutic use for treating, or combating, bacterial infections inmammals, the compounds or pharmaceutical compositions thereof will beadministered orally, parenterally and/or topically at a dosage to obtainand maintain a concentration, that is, an amount, or blood-level ortissue level of active component in the animal undergoing treatmentwhich will be anti-microbially effective. Generally, an effective amountof dosage of active component will be in the range of from about 0.1 toabout 100, more preferably from about 1.0 to about 50 mg/kg of bodyweight/day. The amount administered will also likely depend on suchvariables as the type and extent of disease or indication to be treated,the overall health status of the particular patient, the relativebiological efficacy of the compound delivered, the formulation of thedrug, the presence and types of excipients in the formulation, and theroute of administration. Also, it is to be understood that the initialdosage administered can be increased beyond the above upper level inorder to rapidly achieve the desired blood-level or tissue level, or theinitial dosage can be smaller than the optimum and the daily dosage canbe progressively increased during the course of treatment depending onthe particular situation. If desired, the daily dose can also be dividedinto multiple doses for administration, for example, two to four timesper day.

Various disease states or conditions in humans and other mammals arefound to be caused by or mediated by nonsense or missense mutations.These mutations cause or mediate the disease state or condition byadversely affecting, for example, protein synthesis, folding,trafficking and/or function. Examples of disease states or conditions inwhich an appreciable percentage of the disease or condition is believedto result from nonsense or missense mutations include hemophilia (factorVIII gene), neurofibromatosis (NF1 and NF2 genes), retinitis pigmentosa(human USH2A gene), bullous skin diseases like Epidermolysis bullosapruriginosa (COL7A1 gene), cystic fibrosis (cystic fibrosistransmembrane regulator gene), breast and ovarian cancer (BRCA1 andBRCA2 genes), Duchenne muscular dystrophy (dystrophin gene), coloncancer (mismatch repair genes, predominantly in MLH1 and MSH2), andlysosomal storage disorders such as Neimann-Pick disease (acidsphingomyelinase gene). See Sanders C R, Myers J K. Disease-relatedmisassembly of membrane proteins. Annu Rev Biophys Biomol Struct. 2004;33:25-51; National Center for Biotechnology Information (U.S.) Genes anddisease Bethesda, Md.: NCBI, NLM ID: 101138560; and Raskó, István;Downes, C S Genes in medicine: molecular biology and human geneticdisorders 1st ed. London; New York: Chapman & Hall, 1995. NLM ID:9502404. The compounds of the present invention can be used to treat orprevent a disease state in a mammal caused or mediated by such nonsenseor missense mutations by administering to a mammal in need thereof aneffective amount of the present invention to suppress the nonsense ormissense mutation involved in the disease state.

6. Examples

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (E M Merck, Silica Gel 60,230-400 mesh) unless otherwise noted.

Some of the abbreviations used in the following, experimental details ofthe synthesis of the examples are defined below:

Ac=acetylhr=hour(s)min=minute(s)mol=mole(s)mmol=millimole(s)M=molarμM=micromolarg=gram(s)μg=microgram(s)rt=room temperatureL=liter(s)mL=milliliter(s)Bt₂O=diethyl etherTHF=tetrahydrofuranDMSO=dimethyl sulfoxideEtOAc=ethyl acetateEt₃N=triethylaminei-Pr₂NEt=diisopropylethylamineCH₂Cl₂=methylene chlorideCHCl₃=chloroformCDCl₃=deuterated chloroformCCl₄=carbon tetrachlorideMeOH=methanolCD₃OD=deuterated methanolEtOH=ethanolDMF=dimethylformamideBOC=t-butoxycarbonylCBZ=benzyloxycarbonylTBS=t-butyldimethylsilylTBSCl=i-butyldimethylsilyl chlorideTFA=trifluoroacetic acidDBU=diazabicycloundeceneTBDPSCl=t-butyldiphenylchlorosilane

Hunig's Base=N,N-diisopropylethylamine

DMAP=4-dimethylaminopyridineCuI=copper (I) iodideMsCl=methanesulfonyl chlorideNaN₃=sodium azideNa₂SO₄=sodium sulfateNaIHCO₃=sodium bicarbonateNaOH=sodium hydroxideMgSO₄=magnesium sulfateK₂CO₃=potassium carbonateKOH=potassium hydroxideNH₄OH=ammonium hydroxideNH₄Cl=ammonium chlorideSiO₂=silicaPd—C=palladium on carbonPd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(II)

Exemplary compounds which can be synthesized in accordance with theinvention are listed in Table 1, Table 1A, and Table 1C. A bolded ordashed bond is shown to indicate a particular stereochemistry at achiral center, whereas a wavy bond indicates that the substituent can bein either orientation or that the compound is a mixture thereof. Itshould also be known that in the interest of space, the chemicalstructures for some compounds have been condensed, for example themethyl and ethyl group substituents are designated with just a carbonbackbone representation, and the unsaturated bonds in the triazole ringsmight not always be visible.

The compounds of the present invention can be prepared, formulated, anddelivered as pharmaceutically acceptable salts, esters, and prodrugs.For convenience, the compounds are generally shown without indicating aparticular salt, ester, or prodrug form.

TABLE 1 Compound No. Structure 100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

Table 1A provides further examples of compounds, compounds 1000a-hthrough 1051a-h, of the present invention. These compounds correspond tothe following structure, wherein “T”, “A”, and R¹¹ are as defined belowand in Table 1B. Compounds in which, for example, the —OCH₃ substituentis replaced with —OCH₂F or —SCH₃ can also be prepared and arecontemplated as within the scope of the present invention.

TABLE 1A Compound T A R¹¹ 1000a T1 H H 1000b T1 H F 1000c T2 H H 1000dT2 H F 1000e T3 H H 1000f T3 H F 1000g T4 H H 1000h T4 H F 1001a T1CH₃CH₂CH₂— H 1001b T1 CH₃CH₂CH₂— F 1001c T2 CH₃CH₂CH₂— H 1001d T2CH₃CH₂CH₂— F 1001e T3 CH₃CH₂CH₂— H 1001f T3 CH₃CH₂CH₂— F 1001g T4CH₃CH₂CH₂— H 1001h T4 CH₃CH₂CH₂— F 1002a T1 CH₂═CHCH₂— H 1002b T1CH₂═CHCH₂— F 1002c T2 CH₂═CHCH₂— H 1002d T2 CH₂═CHCH₂— F 1002e T3CH₂═CHCH₂— H 1002f T3 CH₂═CHCH₂— F 1002g T4 CH₂═CHCH₂— H 1002h T4CH₂═CHCH₂— F 1003a T1 HC≡CCH₂— H 1003b T1 HC≡CCH₂— F 1003c T2 HC≡CCH₂— H1003d T2 HC≡CCH₂— F 1003e T3 HC≡CCH₂— H 1003f T3 HC≡CCH₂— F 1003g T4HC≡CCH₂— H 1003h T4 HC≡CCH₂— F 1004a T1

H 1004b T1

F 1004c T2

H 1004d T2

F 1004e T3

H 1004f T3

F 1004g T4

H 1004h T4

F 1005a T1

H 1005b T1

F 1005c T2

H 1005d T2

F 1005e T3

H 1005f T3

F 1005g T4

H 1005h T4

F 1006a T1

H 1006b T1

F 1006c T2

H 1006d T2

F 1006e T3

H 1006f T3

F 1006g T4

H 1006h T4

F 1007a T1

H 1007b T1

F 1007c T2

H 1007d T2

F 1007e T3

H 1007f T3

F 1007g T4

H 1007h T4

F 1008a T1

H 1008b T1

F 1008c T2

H 1008d T2

F 1008e T3

H 1008f T3

H 1008g T4

H 1008h T4

F 1009a T1

H 1009b T1

F 1009c T2

H 1009d T2

F 1009e T3

H 1009f T3

F 1009g T4

H 1009h T4

F 1010a T1

H 1010b T1

F 1010c T2

H 1010d T2

F 1010e T3

H 1010f T3

F 1010g T4

H 1010h T4

F 1011a T1

H 1011b T1

F 1011c T2

H 1011d T2

F 1011e T3

H 1011f T3

F 1011g T4

H 1011h T4

F 1012a T1

H 1012b T1

F 1012c T2

H 1012d T2

F 1012e T3

H 1012f T3

F 1012g T4

H 1012h T4

F 1013a T1

H 1013b T1

F 1013c T2

H 1013d T2

F 1013e T3

H 1013f T3

F 1013g T4

H 1013h T4

F 10140a T1

H 1014b T1

F 1014c T2

H 1014d T2

F 1014e T3

H 1014f T3

F 1014g T4

H 1014h T4

F 1015a T1

H 1015b T1

F 1015c T2

H 1015d T2

F 1015e T3

H 1015f T3

F 1015g T4

H 1015h T4

F 1016a T1 HO— H 1016b T1 HO— F 1016c T2 HO— H 1016d T2 HO— F 1016e T3HO— H 1016f T3 HO— F 1016g T4 HO— H 1016h T4 HO— F 1017a T1 HS— H 1017bT1 HS— F 1017c T2 HS— H 1017d T2 HS— F 1017e T3 HS— H 1017f T3 HS— F1017g T4 HS— H 1017h T4 HS— F 1018a T1 F H 1018b T1 F F 1018c T2 F H1018d T2 F F 1018e T3 F H 1018f T3 F F 1018g T4 F H 1018h T4 F F 1019aT1 Cl H 1019b T1 Cl F 1019c T2 Cl H 1019d T2 Cl F 1019e T3 Cl H 1019f T3Cl F 1019g T4 Cl H 1019h T4 Cl F 1020a T1 Br H 1020b T1 Br F 1020c T2 BrH 1020d T2 Br F 1020e T3 Br H 1020f T3 Br F 1020g T4 Br H 1020h T4 Br F1021a T1 I H 1021b T1 I F 1021c T2 I H 1021d T2 I F 1021e T3 I H 1021fT3 I F 1021g T4 I H 1021h T4 I F 1022a T1 F₃C— H 1022b T1 F₃C— F 1022cT2 F₃C— H 1022d T2 F₃C— F 1022e T3 F₃C— H 1022f T3 F₃C— F 1022g T4 F₃C—H 1022h T4 F₃C— F 1023a T1 NC— H 1023b T1 NC— F 1023c T2 NC— H 1023d T2NC— F 1023e T3 NC— H 1023f T3 NC— F 1023g T4 NC— H 1023h T4 NC— F 1024aT1 N₃— H 1024b T1 N₃— F 1024c T2 N₃— H 1024d T2 N₃— F 1024e T3 N₃— H1024f T3 N₃— F 1024g T4 N₃— H 1024h T4 N₃— F 1025a T1 NO₂— H 1025b T1NO₂— F 1025c T2 NO₂— H 1025d T2 NO₂— F 1025e T3 NO₂— H 1025f T3 NO₂— F1025g T4 NO₂— H 1025h T4 NO₂— F 1026a T1 (CH₃)₂N— H 1026b T1 (CH₃)₂N— F1026c T2 (CH₃)₂N— H 1026d T2 (CH₃)₂N— F 1026e T3 (CH₃)₂N— H 1026f T3(CH₃)₂N— F 1026g T4 (CH₃)₂N— H 1026h T4 (CH₃)₂N— F 1027a T1 CH₃O— H1027b T1 CH₃O— F 1027c T2 CH₃O— H 1027d T2 CH₃O— F 1027e T3 CH₃O— H1027f T3 CH₃O— F 1027g T4 CH₃O— H 1027h T4 CH₃O— F 1028a T1 CH₃S— H1028b T1 CH₃S— F 1028c T2 CH₃S— H 1028d T2 CH₃S— F 1028e T3 CH₃S— H1028f T3 CH₃S— F 1028g T4 CH₃S— H 1028h T4 CH₃S— F 1029a T1 CH₃S(═O)— H1029b T1 CH₃S(═O)— F 1029c T2 CH₃S(═O)— H 1029d T2 CH₃S(═O)— F 1029e T3CH₃S(═O)— H 1029f T3 CH₃S(═O)— F 1029g T4 CH₃S(═O)— H 1029h T4 CH₃S(═O)—F 1030a T1 CH₃S(═O)₂— H 1030b T1 CH₃S(═O)₂— F 1030c T2 CH₃S(═O)₂— H1030d T2 CH₃S(═O)₂— F 1030e T3 CH₃S(═O)₂— H 1030f T3 CH₃S(═O)₂— F 1030gT4 CH₃S(═O)₂— H 1030h T4 CH₃S(═O)₂— F 1031a T1 HC(═O)— H 1031b T1HC(═O)— F 1031c T2 HC(═O)— H 1031d T2 HC(═O)— F 1031e T3 HC(═O)— H 1031fT3 HC(═O)— F 1031g T4 HC(═O)— H 1031h T4 HC(═O)— F 1032a T1 CH₃C(═O)— H1032b T1 CH₃C(═O)— F 1032c T2 CH₃C(═O)— H 1032d T2 CH₃C(═O)— F 1032e T3CH₃C(═O)— H 1032f T3 CH₃C(═O)— F 1032g T4 CH₃C(═O)— H 1032h T4 CH₃C(═O)—F 1033a T1 CH₃OC(═O)— H 1033b T1 CH₃OC(═O)— F 1033c T2 CH₃OC(═O)— H1033d T2 CH₃OC(═O)— F 1033e T3 CH₃OC(═O)— H 1033f T3 CH₃OC(═O)— F 1033gT4 CH₃OC(═O)— H 1033h T4 CH₃OC(═O)— F 1034a T1 CH₃COO— H 1034b T1CH₃COO— F 1034c T2 CH₃COO— H 1034d T2 CH₃COO— F 1034e T3 CH₃COO— H 1034fT3 CH₃COO— F 1034g T4 CH₃COO— H 1034h T4 CH₃COO— F 1035a T1 CH₃OCOO— H1035b T1 CH₃OCOO— F 1035c T2 CH₃OCOO— H 1035d T2 CH₃OCOO— F 1035e T3CH₃OCOO— H 1035f T3 CH₃OCOO— F 1035g T4 CH₃OCOO— H 1035h T4 CH₃OCOO— F1036a T1 CH₃C(═O)S— H 1036b T1 CH₃C(═O)S— F 1036c T2 CH₃C(═O)S— H 1036dT2 CH₃C(═O)S— F 1036e T3 CH₃C(═O)S— H 1036f T3 CH₃C(═O)S— F 1036g T4CH₃C(═O)S— H 1036h T4 CH₃C(═O)S— F 1037a T1 CH₃C(═O)NH— H 1037b T1CH₃C(═O)NH— F 1037c T2 CH₃C(═O)NH— H 1037d T2 CH₃C(═O)NH— F 1037e T3CH₃C(═O)NH— H 1037f T3 CH₃C(═O)NH— F 1037g T4 CH₃C(═O)NH— H 1037h T4CH₃C(═O)NH— F 1038a T1 CH₃NHC(═O)— H 1038b T1 CH₃NHC(═O)— F 1038c T2CH₃NHC(═O)— H 1038d T2 CH₃NHC(═O)— F 1038e T3 CH₃NHC(═O)— H 1038f T3CH₃NHC(═O)— F 1038g T4 CH₃NHC(═O)— H 1038h T4 CH₃NHC(═O)— F 1039a T1CH₃C(═NOH)— H 1039b T1 CH₃C(═NOH)— F 1039c T2 CH₃C(═NOH)— H 1039d T2CH₃C(═NOH)— F 1039e T3 CH₃C(═NOH)— H 1039f T3 CH₃C(═NOH)— F 1039g T4CH₃C(═NOH)— H 1039h T4 CH₃C(═NOH)— F 1040a T1 CH₃C[═N—N(CH₃)₂]— H 1040bT1 CH₃C[═N—N(CH₃)₂]— F 1040c T2 CH₃C[═N—N(CH₃)₂]— H 1040d T2CH₃C[═N—N(CH₃)₂]— F 1040e T3 CH₃C[═N—N(CH₃)₂]— H 1040f T3CH₃C[═N—N(CH₃)₂]— F 1040g T4 CH₃C[═N—N(CH₃)₂]— H 1040h T4CH₃C[═N—N(CH₃)₂]— F 1041a T1

H 1041b T1

F 1041c T2

H 1041d T2

F 1041e T3

H 1041f T3

F 10410g T4

H 1041h T4

F 1042a T1 CH₃C[═N—OCH₃]— H 1042b T1 CH₃C[═N—OCH₃]— F 1042c T2CH₃C[═N—OCH₃]— H 1042d T2 CH₃C[═N—OCH₃]— F 1042e T3 CH₃C[═N—OCH₃]— H1042f T3 CH₃C[═N—OCH₃]— F 1042g T4 CH₃C[═N—OCH₃]— H 1042h T4CH₃C[═N—OCH₃]— F 1043a T1 CH₃OC(═O)NH— H 1043b T1 CH₃OC(═O)NH— F 1043cT2 CH₃OC(═O)NH— H 1043d T2 CH₃OC(═O)NH— F 1043e T3 CH₃OC(═O)NH— H 1043fT3 CH₃OC(═O)NH— F 1043g T4 CH₃OC(═O)NH— H 1043h T4 CH₃OC(═O)NH— F 1044aT1 CH₃NHC(═O)O— H 1044b T1 CH₃NHC(═O)O— F 1044c T2 CH₃NHC(═O)O— H 1044dT2 CH₃NHC(═O)O— F 1044e T3 CH₃NHC(═O)O— H 1044f T3 CH₃NHC(═O)O— F 1044gT4 CH₃NHC(═O)O— H 1044h T4 CH₃NHC(═O)O— F 1045a T1 CH₃NHC(═O)NH— H 1045bT1 CH₃NHC(═O)NH— F 1045c T2 CH₃NHC(═O)NH— H 1045d T2 CH₃NHC(═O)NH— F1045e T3 CH₃NHC(═O)NH— H 1045f T3 CH₃NHC(═O)NH— F 1045g T4 CH₃NHC(═O)NH—H 1045h T4 CH₃NHC(═O)NH— F 1046a T1 CH₃S(═O)₂NH— H 1046b T1 CH₃S(═O)₂NH—F 1046c T2 CH₃S(═O)₂NH— H 1046d T2 CH₃S(═O)₂NH— F 1046e T3 CH₃S(═O)₂NH—H 1046f T3 CH₃S(═O)₂NH— F 1046g T4 CH₃S(═O)₂NH— H 1046h T4 CH₃S(═O)₂NH—F 1047a T1 CH₃NHS(═O)₂— H 1047b T1 CH₃NHS(═O)₂— F 1047c T2 CH₃NHS(═O)₂—H 1047d T2 CH₃NHS(═O)₂— F 1047e T3 CH₃NHS(═O)₂— H 1047f T3 CH₃NHS(═O)₂—F 1047g T4 CH₃NHS(═O)₂— H 1047h T4 CH₃NHS(═O)₂— F 1048a T1 NH₂— H 1048bT1 NH₂— F 1048c T2 NH₂— H 1048d T2 NH₂— F 1048e T3 NH₂— H 1048f T3 NH₂—F 1048g T4 NH₂— H 1048h T4 NH₂— F 1049a T1 (CH₃)₂N— H 1049b T1 (CH₃)₂N—F 1049c T2 (CH₃)₂N— H 1049d T2 (CH₃)₂N— F 1049e T3 (CH₃)₂N— H 1049f T3(CH₃)₂N— F 1049g T4 (CH₃)₂N— H 1049h T4 (CH₃)₂N— F 1050a T1 (CH₃)₃Si— H1050b T1 (CH₃)₃Si— F 1045c T2 (CH₃)₃Si— H 1050d T2 (CH₃)₃Si— F 1050e T3(CH₃)₃Si— H 1050f T3 (CH₃)₃Si— F 1050g T4 (CH₃)₃Si— H 1050h T4 (CH₃)₃Si—F 1051a T1 (CH₃O)₃Si— H 1051b T1 (CH₃O)₃Si— F 1051c T2 (CH₃O)₃Si— H1051d T2 (CH₃O)₃Si— F 1051e T3 (CH₃O)₃Si— H 1051f T3 (CH₃O)₃Si— F 1051gT4 (CH₃O)₃Si— H 1051h T4 (CH₃O)₃Si— F

In the forgoing Table 1A, T1, T2, T3, and T4 correspond to the followingstructures as defined below in Table 1B:

TABLE 1B T T1

T2

T3

T4

Table 1C provides further examples of compounds of the presentinvention. These compounds correspond to the following structure,wherein “A” is as defined in Table IC, below. Note that the fragmentsfor “A” are drawn such that the fragment is bonded to the phenyl ring inthe structure below via the bond on the left. For example, the firstfragment,

could alternatively be drawn as

or —CH₂—CF₃.

TABLE 1C A Groups. Connection is to bond on left.

—Br

—Cl

Synthesis of the Compounds of the Present Invention

Compounds of the present invention can be made, for example, via acycloaddition reaction of an alkynyl macrolide with an azide compound.In this cycloaddition reaction, the triazole functional group of theresulting compound is formed. Other compounds of the present inventionare made by further chemically modifying the resulting compound from thecycloaddition reaction.

The cycloaddition reaction is generally run in the presence of a copper(I) salt such as copper iodide (CuI). A base can also be optionallyused, such as Hunig's base (N,N-diisopropylethylamine). The followinggeneral reaction scheme outlines the cycloaddition reaction of thealkynyl macrolide and the azide compound.

The time required for the reaction to proceed to completion is variableand is dependent upon several factors including: the specific alkynylmacrolide and azide compounds and their concentrations; the amount ofCu(I) salt used; and the presence or absence of base, such as Hunig'sBase(N,N-diisopropylethylamine). Reactions are monitored for thedisappearance of the starting materials by TLC and/or LCMS and aretypically allowed to run for between about 2 hours to about 72 hours.Reactions are generally stopped when analysis demonstrates that thestarting alkynyl macrolide has been substantially consumed. The workupand purification protocols are standard. Modifications to the describedworkup procedures can be used. Such modifications can include the use ofdifferent aqueous wash solutions, different organic solvents forextraction, the use of other anhydrous salts for the drying of organicextracts, and the employment of different solvent mixtures for thechromatographic purification of the compounds. The methods used for theworkup of the reaction mixtures, the extraction of products, the dryingof organic extracts, and for the isolation and purification of the titlecompounds are typical of procedures familiar to those trained in the artof organic synthesis. The isolated chemical yields for the synthesis ofcompounds can be variable and are indicated in Table 2.

Most compounds of the present invention can be prepared from the desiredalkynyl macrolide and azide compound under one of several similarreaction conditions as exemplified by Conditions A, B, C, and D below.Use of Conditions A and C, which do not include the step of degassingthe reaction mixture, tend to result in the formation of iodinatedside-products in addition to the desired product and thereby generallyproduced lower isolated yields. Additionally, reduction of the amount ofcopper iodide used in the reaction to 0.5 molar equivalents or less asin conditions B and D also tends to result in reduced formation ofiodinated by-products. As demonstrated in Condition D, the presence ofHunig's base is not essential for the success of the triazole formationstep; however, it is found preferable that the base be included since itoften results in a higher rate of reaction and correspondingly shorterreaction times.

Condition A:

To a stirred solution of the alkynyl macrolide (0.04 mmol), the azidecompound (0.07 mmol) and Hunig's base (10 μL) in 0.5 mL tetrahydrofuran(THF) is added CuI (5 mg, 0.03 mmol). The mixture is stirred at ambienttemperature for 16 hours then diluted with CH₂Cl₂ (10 mL) and washedwith a 3:1 mixture of saturated aqueous NH₄Cl and 28% aqueous NH₄OH (10mL) and with brine (10 mL) the aqueous washes are back-extracted withCH₂Cl₂ (2×10 mL). The combined organic extracts are dried over K₂CO₃,filtered, and concentrated to afford 52 mg of crude product which ispurified by chromatography on silica gel (elution with 40:1 2M NH₃ inMeOH and CH₂Cl₂) to give the desired compound.

Condition B:

A solution of alkynyl compound (0.10 mmol) and azide compound (0.12mmol) and Hunig's base in 0.4 mL THF are thoroughly degassed byalternately evacuating the reaction vessel and purging with dry argon.CuI is then added (2 mg, 0.01 mmol) and the mixture is further degassed.The mixture is stirred under argon for 6 h then diluted with CH₂Cl₂ (20mL) and washed with a 3:1 mixture of saturated aqueous NH₄Cl and 28%aqueous NH₄OH (10 mL) and with brine (10 mL) the aqueous washes areback-extracted with CH₂Cl₂ (2×15 mL). The combined organic extracts weredried over K₂CO₃, filtered, and concentrated to afford 115 mg of crudeproduct which is purified by chromatography on silica gel (eluted with2M NH₃ in MeOH (2.5%) and CH_(z)Cl₂ (97.5%), to give the desiredcompound.

Condition C:

To a stirred solution of alkynyl compound (0.10 mmol) and Hunig's base(0.2 mL) in 3 mL THF is added the azide compound (0.50 mmol) and CuI (20mg, 0.10 mmol). The reaction mixture is stirred under argon for 60 hoursthen poured into saturated aqueous NH₄Cl and extracted with CH₂Cl₂. Theorganic extracts are dried over Na₂SO₄, filtered, and concentrated toafford a crude residue which is purified by silica gel chromatography(eluted with 25:1:0.1 CH₂Cl₂:MeOH:NH₄OH) and then by preparative TLC(elution with 25:1:0.1 CH₂Cl₂:MeOH:NH₄OH) to afford the desiredcompound.

Condition D

A solution of alkynyl compound (0.15 mmol) and the azide compound (0.25mmol) in 2.7 mL THF are thoroughly degassed by alternately evacuatingthe reaction vessel and purging with dry argon. CuI is then added (10mg, 0.05 mmol) and the mixture is further degassed. The mixture isstirred under argon for 4 h then concentrated in vacuo, dissolved inCH₂Cl₂ (1 mL), and placed directly on a silica gel column. Elution with2 molar (M) NH₃ in MeOH (3%) and CH₂Cl₂ (97%) gives the desiredcompound. Synthesis of Compounds Wherein Substituent “A” Contains aTriazole Ring Compounds 131, 132, 172, 173, 174, 175, 182, 185, 199,201, 203, and 205, as well as other similar compounds, correspond to thegeneric structure wherein substituent A, as defined for the compounds ofthe present invention, contains a triazole ring. For Compounds 131, 132,172, 173, 174, 175, 182, 185, 199, 201, 203, and 205, (R¹¹)_(n) ishydrogen, i.e. the phenyl ring is only substituted with A. Thesecompounds are generally prepared from the cycloaddition reaction of thedesired alkynyl macrolide and the nitro phenylazide compound to form theresulting nitro phenyl macrolide compound. This nitro phenyl macrolidecompound is then further transformed to yield the desired compound. Forcompounds 131, 132, 172, 173, 174, 175, 182, 185, 199, 201, 203, and205, the nitro group is converted to an azide group via an amine. Theazide group is then reacted with an appropriately functionalized alkynein a second cycloaddition reaction to form the desired compound.

Further detail for some of the compounds of the present invention areprovided in Table 2, which are organized as follows:

The first column (labeled “Compound”) lists compound numberscorresponding to those of Table 1, above.

The second column (labeled “Alkynyl Macrolide”) corresponds to thealkynyl macrolide compounds that can be used in the synthesis of thecompounds of the present invention. Nonlimiting examples of alkynylmacrolide compounds, labeled. M1 to M28 are separately shown below inTable 3.

The third column (labeled “Azide”) corresponds to the azide compoundsthat can be used in the synthesis of the compounds of the presentinvention. It should be noted that compounds 131, 132, 172, 173, 174,175, 182, 185, 199, 201, 203, and 205, as well as other similarcompounds, are prepared via a common nitro phenyl azide intermediate, X.The nitro group is further transformed after the cycloaddition reactionto produce the final desired product.

The fourth column (labeled “Yield”) provides the percent yieldcorresponding to the cycloaddition reaction of the alkynyl macrolide andthe azide compound for the indicated compound. In the case of compounds131, 132, 172, 173, 174, 175, 182, 185, 199, 201, 203, and 205, theyield is a general average for the reaction of the alkynyl macrolide andnitro phenyl azide X.

The fifth column (labeled “LCMS”) provides the liquid chromatographymass spectral data, where available, for the compound.

TABLE 2 Alkynyl Compound Macrolide Azide LCMS 100 M1

 538.2 (M + 2H)²⁺ 101 M1

 537.7 (M + 2H)²⁺ 102 M1

 552.6 (M + 2H)²⁺ 103 M1

 538.2 (M + 2H)²⁺ 104 M1

 544.6 (M + 2H)²⁺ 105 M1

 538.2 (M + 2H)²⁺ 106 M1

 545.675 (M + 2H)²⁺ 107 M1

 532.6 (M + 2H)²⁺ 108 M1

 572.7 (M + 2H)²⁺ 109 M1

 552.6 (M + 2H)²⁺ 110 M1

 562.1 (M + 2H)²⁺ 111 M1

 499.1 (M + 2H)²⁺ 112 M1

 539.2 (M + 2H)²⁺ 113 M1

 551.7 (M + 2H)²⁺ 114 M1

 552.2 (M + 2H)²⁺ 115 M2

— 116 M1

 532.2 (M + 2H)²⁺ 117 M1

 532.2 (M + 2H)²⁺ 118 M1

 532.2 (M + 2H)²⁺ 119 M1

 532.1 (M + 2H)²⁺ 120 M3

1063.0 (M + H)⁺ 121 M1

 555.2 (M + 2H)²⁺ 122 M3

1074.1 (M + H)⁺ 123 M3

 552.2 (M + 2H)²⁺ 124 M3

1073.3 (M + H)⁺ 125 M1

 541.2 (M + 2H)²⁺ 126 M3

1087 (M + H)⁺ 127 M4

 955 (M + 2)⁺ 128 M5

 913 (M + H)⁺ 129 M1

 521.6 (M + 2H)²⁺ 130 M1

 540.7 (M + 2H)²⁺ 131 M1

 568.7 (M + 2H)²⁺ 132 M1

 532.7 (M + 2H)²⁺ 133 M3

1088.8 (M + H)⁺ 134 M1

 545.7 (M + 2H)²⁺ 135 M1

 548.2 (M + 2H)²⁺ 136 M3

1093.8 (M + H)⁺ 137 M5

 934 (M + H)⁺ 138 M3

 914 (M + H)⁺ 139 M1

 536.1 (M + 2H)²⁺ 140 M1

 529.2 (M + 2H)²⁺ 141 M1

 537.2 (M + 2H)²⁺ 142 M1

 545.2 (M + 2H)²⁺ 143 M1

 534.7 (M + 2H)²⁺ 144 M1

 527.7 (M + 2H)²⁺ 145 M1

 520.6 (M + 2H)²⁺ 146 M1

 541.6 (M + 2H)²⁺ 147 M3

 541.2 (M + 2H)²⁺ 148 M1

 562.2 (M + 2H)²⁺ 149 M1

 540.7 (M + 2H)²⁺ 150 M1

 552.7 (M + 2H)²⁺ 151 M1

 555.2 (M + 2H)²⁺ 152 M1

 588.2 (M + 2H)²⁺ 153 M1

 549.2 (M + 2H)²⁺ 154 M1

 548.7 (M + 2H)²⁺ 155 M1

 579.7 (M + 2H)²⁺ 156 M1

 545.7 (M + 2H)²⁺ 157 M1

 541.7 (M + 2H)²⁺ 158 M1

 569.8 (M + 2H)²⁺ 159 M1

 565.7 (M + 2H)²⁺ 160 M1

 528.2 (M + 2H)²⁺ 161 M1

 560.5 (M + 2H)²⁺ 162 M1

 540.7 (M + 2H)²⁺ 163 M1

 506.6 (M + 2H)²⁺ 164 M1

 513.1 (M + 2H)²⁺ 165 M1

 521.1 (M + 2H)²⁺ 166 M1

 514.1 (M + 2H)²⁺ 167 M1

 548.6 (M + 2H)²⁺ 168 M1

 536 (M + 2H)²⁺ 169 M1

 552 (M + 2H)²⁺ 170 M1

 534.5 (M + 2H)²⁺ 171 M1

 550.5 (M + 2H)²⁺ 172 M1

 547.8 (M + 2H)²⁺ 173 M1

 561.2 (M + 2H)²⁺ 174 M1

 569.8 (M + 2H)²⁺ 175 M1

 554.3 (M + 2H)²⁺ 176 M1

 548.7 (M + 2H)²⁺ 177 M1

 527.7 (M + 2H)²⁺ 178 M1

 527.7 (M + 2H)²⁺ 179 M1

 527.2 (M + 2H)²⁺ 180 M1

 555.7 (M + 2H)²⁺ 181 M1

 534.6(M + 2H)²⁺ 182 M1

 552.8 (M + 2H)²⁺ 183 M1

 554.7 (M + 2H)²⁺ 184 M1

 519.7 (M + 2H)²⁺ 185 M1

 606.3 (M + 2H)²⁺ 186 M1

 537.1 (M + 2H)²⁺ 187 M1

 544.1 (M + 2H)²⁺ 188 M1

 555.1 (M + 2H)²⁺ 189 M1

 529.1 (M + 2H)²⁺ 190 M1

 545.1 (M + 2H)²⁺ 191 M1

 523.3 (M + 2H)²⁺ 192 M1

 552.7 (M + 2H)²⁺ 193 M1

 549.2 (M + 2H)²⁺ 194 M1

 549.1 (M + 2H)²⁺ 195 M1

 541.8 (M + 2H)²⁺ 196 M1

 558.5 (M + 2H)²⁺ 197 M1

 547.1 (M + 2H)²⁺ 198 M1

 520.6 (M + 2H)²⁺ 199 M1

 560.9 (M + 2H)²⁺ 200 M1

 538.5 (M + 2H)²⁺ 201 M1

 561.1 (M + 2H)²⁺ 202 M1

 545.7 (M + 2H)²⁺ 203 M1

 554.8 (M + 2H)²⁺ 204 M1

 565.2 (M + 2H)²⁺ 205 M1

 567.8 (M + 2H)²⁺ 206 M1

 557.2 (M + 2H)²⁺ 207 M1

 564.2 (M + 2H)²⁺ 208 M1

 552.1 (M + 2H)²⁺ 209 M1

 572.2 (M + 2H)²⁺ 210 M1

 580.2 (M + 2H)²⁺ 211 M6

1113.4 (M + H)⁺ 212 M6

1142.4 (M + H)⁺ 213 M7

1099.4 (M + H)⁺ 214 M7

1128.4 (M + H)⁺ 215 M8

1143.4 (M + H)⁺ 216 M8

1172.4 (M + H)⁺ 217 M1

 543.6 (M + 2H)²⁺ 218 M1

 559.8 (M + 2H)²⁺ 219 M1

 547.2 (M + 2H)²⁺ 220 M1

 511.0 (M + 2H)²⁺ 221 M1

 550.5 (M + 2H)²⁺ 222 M1

 542.1 (M + 2H)²⁺ 223 M1

 552.5 (M + 2H)²⁺ 224 M1

 511.6 (M + 2H)²⁺ 225 M1

 558.7 (M + 2H)²⁺ 226 M1

 566.6 (M + 2H)²⁺ 227 M1

 573.6 (M + 2H)²⁺ 228 M1

 565.6 (M + 2H)²⁺ 229 M1

 584.1 (M + 2H)²⁺ 230 M1

 573.1 (M + 2H)²⁺ 231 M1

 572.5 (M + 2H)²⁺ 232 M1

 564.2 (M + 2H)²⁺ 233 M1

 547.1 (M + 2H)²⁺ 234 M1

 539.1 (M + 2H)²⁺ 235 M1

 546.6 (M + 2H)²⁺ 236 M1

 540.3 (M + 2H)²⁺ 237 M1

 558.3 (M + 2H)²⁺ 238 M1

 541.1 (M + 2H)²⁺ 239 M1

 522.2 (M + 2H)²⁺ 240 M1

 530.1 (M + 2H)²⁺ 241 M1

 553.0 (M + 2H)²⁺ 242 M1

 545.1 (M + 2H)²⁺ 243 M1

 560.1 (M + 2H)²⁺ 244 M1

 572.4 (M + 2H)²⁺ 245 M1

 541.3 (M + 2H)²⁺ 246 M1

 570.2 (M + 2H)²⁺ 247 M1

 557.1 (M + 2H)²⁺ 248 M1

 553.7 (M + 2H)²⁺ 249 M1

 619.9 (M + 2H)²⁺ 250 M1

 540.8 (M + 2H)²⁺ 251 M1

 533.7 (M + 2H)²⁺ 252 M1

 513.7 (M + 2H)²⁺ 253 M1

 578.8 (M + 2H)²⁺ 254 M1

 557.2 (M + 2H)²⁺ 255 M1

 538.1 (M + 2H)²⁺ 256 M1

 545.2 (M + 2H)²⁺ 257 M1

 539.8 (M + 2H)²⁺ 258 M1

 589.8 (M + 2H)²⁺ 259 M1

 560.7 (M + 2H)²⁺ 260 M1

 547.1 (M + 2H)²⁺ 261 M1

 419.9 (M + 3H)³⁺  629.5 (M + 2H)²⁺ 262 M1

 527.3 (M + 2H)²⁺ 263 M1

 548.1 (M + 2H)²⁺ 264 M1

 568.6 (M + 2H)²⁺ 265 M27

1039.3 (M + H)⁺ 266 M1

 527.7 (M + 2H)²⁺ 267 M1

 544.8 (M + 2H)²⁺ 268 M1

 546.1 (M + 2H)²⁺ 269 M1

 561.3 (M + 2H)²⁺ 270 M1

 553.1 (M + 2H)²⁺ 271 M1

 577.3 (M + 2H)²⁺ 272 M1

 541.6 (M + 2H)²⁺ 273 M1

 541.8 (M + 2H)²⁺ 274 M1

 542.8 (M + 2H)²⁺ 275 M1

 542.8 (M + 2H)²⁺ 276 M1

 551.8 (M + 2H)²⁺ 277 M1

 551.1 (M + 2H)²⁺ 278 M1

 558.3 (M + 2H)²⁺ 279 M1

 556.2 (M + 2H)²⁺ 280 M1

 564.3 (M + 2H)²⁺ 281 M1

 540.6 (M + 2H)²⁺

The alkynyl macrolide compounds that can be used in the synthesis of thecompounds of the present invention are shown in the following Table 3.It is appreciated by one of skill in the art that these alkynylmacrolide compounds, M1 to M28, are nonlimiting examples and that a widevariety of additional alkynyl macrolides can be used to prepare othercompounds of the present invention.

TABLE 3 Alkynyl Macrolide Compound Structure M1

M2

M3

M4

M5

M6

M7

M8

M9

M10

M11

M12

M13

M14

M15

M16

M17

M18

M19

M20

M21

M22

M23

M24

M25

M26

M27

M28

Synthesis of Alkynyl Macrolides

The alkynyl macrolide compounds, such as alkynyl macrolide compounds M1to M28, are generally made by the alkynylation (i.e. the addition of analkynyl group) to a monomethyl amine macrolide compound. The monomethylamine macrolide is generally made by the demethylation of thecorresponding macrolide compound. Depending on the macrolide compoundand functional groups present, the demethylation process can involveseveral steps, including various protection and deprotection steps. Thedesmethyl macrolide compound is alkynylated with the correspondingalkynyl compound, which is generally an alkynyl halide, tosylate, ormesylate. For the compounds of the present invention, 4-bromo-1-butyne,4-iodo-1-butyne, or the tosylate or mesylate of 1-butyn-4-ol aregenerally used. Examples of synthetic procedures for preparing alkynylmacrolides are found in PCT Application No. WO 2005/085266, publishedSep. 15, 2005, to Rib-X Pharmaceuticals, Inc. The following generalreaction scheme outlines this alkynylation process.

The following procedures outline the synthesis of various alkynylmacrolide compounds of the present invention.

Synthesis of Alkynyl Macrolide M1

Alkynyl macrolide M1 is made by selective demethylation of azithromycin1 to produce 3′-N-desmethylazithromycin 2. This compound 2 isselectively alkylated with alkynyl tosylate 11 to produce alkynylmacrolide M1.

Synthesis of 3′-N-Desmethylazithromycin 2

Azithromycin 1 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g,8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution washeated to 50° C. followed by addition of iodine (I₂) (0.272 g, 1.07mmol) in three batches within 3 minutes. The reaction was maintained ata pH between 8 and 9 by adding 1N sodium hydroxide (NaOH) (1 mL) at 10min and 45 minute intervals. The solution turned colorless within 45minutes. Stirring was continued, for 2 hours. TLC (CH₂Cl₂/MeOH/NH₄OH10:1:0.05) after 2 hours showed a single major product (Rf=0.66). Thereaction was cooled to room temperature, poured into H₂O (75 mL)containing NH₄OH (1.5 mL) and extracted with CHCl₃ (3×30 mL). Thecombined organic layers were washed with H₂O (30 mL) containing NH₄OH(1.5 mL), dried over Na₂SO₄ and the solvent evaporated to give a whiteresidue. The crude was purified on a silica gel column eluting withCH₂Cl₂/MeOH/NH₄OH 18:1:0.05 to 10:1:0.05 to provide compound 2 (0.41 g,55%).

Synthesis of Alkynyl Macrolide M1

A mixture of 3′-N-desmethylazithromycin 2 and tosylate 11 in Hunig'sbase was stirred. The reaction mixture was diluted to EtOAc and washedwith NaHCO₃(aq) and with brine. The organic layer was dried over K₂CO₃and the solvent was evaporated to give product. The crude product waspurified on silica gel column to give M1 as a white solid.

Synthesis of Alkynyl Macrolide M3.

Synthesis of 3′-N-Desmethyl-Clarithromycin 21

To a mixture of clarithromycin (1.00 g, 1.3 mmol) and NaOAc.3H₂O (0.885g, 6.5 mmol) was added MeOH—H₂O (20 mL, 4:1), and the mixture heated to55-60° C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and thereaction stirred at 55-60° C. for 3 h. The reaction mixture was pouredinto 50 mL CHCl₃ containing 1 mL ammonium hydroxide. It was extractedwith CHCl₃ (4×50 mL), washed with water (70 mL) containing 5 mL ammoniumhydroxide, dried (anhydrous Na₂SO₄), concentrated, and purified by flashchromatography (silica gel, CHCl₃:MeOH:NH₄OH 100:10:0.1) to afford 21.Yield: 0.9 g (92%).

Synthesis of Alkynyl Macrolide M3

A mixture of 3′-N-desmethyl-clarithromycin 21 and tosylate 11 inanhydrous THF and Hunig's base was stirred. The reaction was poured intoCH₂Cl₂, extracted with 2% aqueous NH₄OH and saturated brine. The organiclayer was dried over Na₂SO₄ and the solvent was evaporated away. Thecrude was purified on a silica gel column to give M3.

Synthesis of Alkynyl Macrolide M14

Alkynyl macrolide M14 is made using a procedure analogous to that formaking M3, starting from erythromycin A. The 3′-N-desmethyl-erythromycinA intermediate is made using a procedure described in U.S. Pat. No.3,725,385, to Freiberg, issued Apr. 3, 1973. Alkynyl macrolide M14 canfurther be used to prepare a variety of macrolides analogous to thosealready depicted for the clarithromycin core.

A mixture of 3′-N-desmethyl-erythromycin (1.0 g, 1.4 mmol) and thetosylate of 1-butyn-4-ol (1.25 g, 5.6 mmol) in anhydrous THF (15 mL) andHunig's base (2.2 mL, 11.9 mmol) was kept stirring at 55° C. for 48hours. The reaction was poured into CH₂Cl₂ (50 mL), extracted with 2%aqueous NH₄OH (3×30 mL) and saturated brine (1×30 mL). The organic layerwas dried over Na₂SO₄ and the solvent was evaporated away. The crude waspurified on a silica gel column eluting with CH₂Cl₂/MeOH 10:1 to givealkynyl macrolide 14 (0.35 g, 32%).

Synthesis of Alkynyl Macrolides M4, M9, M10, M11 and M12

The synthesis of alkynyl macrolides M4, M9, M10, M11 and M12 aredepicted in the scheme below. Alkynyl macrolide M9 is prepared from theremoval of the cladinose sugar of alkynyl macrolide M3 under acidicconditions: Alkynyl macrolide M10 is made by the acetylation ofmacrolide M9. Macrolide M4 is made by the oxidation of the hydroxylgroup of macrolide M10. Alkynyl macrolides M11 and M12 are made byconverting a keto group of alkynyl macrolide M4 to the desired oximes.The oxime functionality of alkynyl macrolides of precursors withsubstituted oxime functionality at the 9-position of the macrocyclicring were prepared from alkyne M3 and as shown below.

Synthesis of Alkynyl Macrolide M9

To the alkynyl macrolide M3 (0.700 g) was added 10 mL 0.9N HCl and themixture was stirred for 4 h at room temperature. The reaction mixturewas saturated with sodium chloride and was adjusted to pH 8 usingaqueous NH₄OH solution. The solution was extracted with ethyl acetate(3×30 mL), dried (with Na₂SO₄), and concentrated under reduced pressure.Purification of the crude reaction mixture by flash chromatography(silica gel, 60% ethyl acetate in hexane) afforded 0.200 g (35% yield)of the descladinose alkynyl macrolide M9. Data for M9; ¹HNMR (300 MHz,CDCl₃, partial): δ 0.82 (t, 3H), 2.25 (s, 3H), 3.00 (s; 3H), 3.25 (dd,1H), 3.55 (m, 2H), 3.70 (s, 1H), 3.85 (s, 1H), 3.95 (s, 1H), 4.40 (d,1H), 5.15 (dd, 1H).

Synthesis of Alkynyl Macrolide M5

A solution of alkynyl macrolide M4 (1 g, 1.5 mmol) in MeOH (30 mL) wasrefluxed for 12 h. The solution was concentrated and the crude materialwas purified by flash chromatography over silica gel (50% ethyl acetatein hexane). Yield: 0.5 g of M5 (53%).

Synthesis of Alkynyl Macrolide M10

To a solution of alkynyl macrolide M9 (0.200 g, 0.32 mmol) in acetone (2mL) was added acetic anhydride (0.050 mL, 0.5 mmol) and the mixture wasstirred overnight at room temperature. The reaction was quenched withwater and extracted with ethyl acetate (3×50 mL). The combined organicfractions were washed with saturated sodium bicarbonate (3×50 mL), dried(anhydrous Na₂SO₄), and concentrated under reduced pressure. The crudereaction mixture was purified by flash chromatography (silica gel, 50%ethyl acetate in hexane) to yield 0.100 g (50% yield) of acetatefunctionalized alkynyl macrolide M10. Data for M10: ¹HNMR (300 MHz,CDCl₃, partial): δ 0.84 (t, 3H), 2.00 (s, 3H), 2.20 (s, 3H), 2.90 (s,3H), 3.00 (q, 1H), 3.25 (s, 1H, 3.47 (m, 2H), 3.70 (bs, 1H), 3.82 (bs,1H), 3.97 (s, 1H), 4.60 (d, 1H), 4.77 (dd, 1H), 5.15 (dd, 1H).

Synthesis of Alkynyl Macrolide M4

To a solution of alkynyl macrolide M10 (0.090 g, 0.134 mmol), EDC.HCl(0.172 g, 0.90 mmol), and DMSO (0.171 mL, 2.41 mmol) in CH₂Cl₂ (1.5 mL)was added dropwise a solution of pyridinium trifluoroacetate (0.174 g,0.90 mmol) in CH₂Cl₂ (1 mL) at 15° C. The reaction mixture was slowlywarmed up to room temperature and stirred for 3 h. The reaction wasquenched with water (2 mL), and allowed to stir for 30 min. The mixturewas then poured into CHCl₃ (50 mL), and the organic layer was washedwith water (2×50 mL), dried (over anhydrous Na₂SO₄), and concentratedunder reduced pressure. The crude material was purified by flashchromatography (silica gel, 30% ethyl acetate in hexane) to yield 0.070g (78%) of the alkynyl macrolide M4 (also commonly referred to as aketolide). Data for M4:M4 MS (ESI) m/e 668 (M+H)⁺; ¹HNMR (300 MHz,CDCl₃, partial): δ 0.86 (t, 3H), 2.00 (s, 3H), 2.24 (s, 3H), 2.70 (s,3H), 2.95-3.10 (m, 1H), 3.15-3.05 (m, 1H), 3.45-3.65 (m, 1H), 3.80 (q,1H), 3.90 (s, 1H), 4.28 (d, 1H), 4.40 (d, 1H), 4.76 (dd, 1H), 5.10 (dd,1H).

Synthesis of Alkynyl Macrolide M11

To a solution of M4 (2.0 g, 2.9 mmol) in MeOH (10 mL) was added(R)—N-Piperidin-3-yl-hydroxylamine hydrobromide (1.26 g, 4.4 mmol). Thereaction mixture was stirred at rt for 14 h. The mixture was then pouredinto (50 mL) and water (50 mL) the pH was adjusted to 11 by addition ofNH₄OH and the organic layer was separated and washed with brine (50 mL),dried (over anhydrous Na₂SO₄), and concentrated under reduced pressure.The crude material was purified by flash chromatography (silica gel,12:1 CH₂Cl₂ and 2M methanolic ammonia) to yield 2 g (78%) of the oximefunctionalized alkynyl macrolide M11 as a 1:1 mixture of E/Z isomers.Data for M11: MS (ESI) m/e 724.7 (M+H).

Synthesis of Alkynyl Macrolide M12

Alkynyl macrolide M12 was synthesized from alkynyl macrolide M4 and(R)—N-Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditionsdescribed above for the synthesis of alkynyl macrolide M11. Data forM12: MS (ESI) m/e 710.6 (M+H)⁺.

Synthesis of Alkynyl Macrolides M13, M16, M17, and M18

Alkynyl macrolides M13, M16, and M17 are also synthesized from alkynylmacrolide M4. Alkynyl macrolide M18 is synthesized from alkynylmacrolide M17. The syntheses are outlined in the following reactionscheme.

Synthesis of Alkynyl Macrolide M13

Alkynyl macrolide M13 was synthesized from alkynyl macrolide M4 andN-[2-dimethtylanminoethyl]-hydroxylamine hydrobromide using theconditions described above for the synthesis of oxime M11. Data for M13:MS (ESI) m/e 726.5 (M+H)⁺.

Synthesis of Alkynyl Macrolide M16

Alkynyl macrolide M16 was synthesized from alkyne M4 andN-Piperidin-4-yl-hydroxyalanine hydrobromide using the conditionsdescribed above for the synthesis of oxime M11. Data for M16: MS (ESI)m/e 724.6 (M+H)⁺.

Synthesis of Alkynyl Macrolide M17

Alkynyl macrolide M17 was synthesized from alkyne M4 andcis-4-aminocyclohexyl-hydroxylamine hydrobromide using the conditionsdescribed above for the synthesis of oxime M11. Data for M17: MS (ESI)m/e 738.7 (M+H)⁺

Synthesis of Alkynyl Macrolide M18

To a solution of alkynyl macrolide M17 (20 mg, 0.02 mmol) in CHCl₃ (0.2mL) was added formaldehyde (5 mg of 37% aqueous solution, 0.06 mmol) andformic acid (6 mg, 0.12 mmol). The mixture was heated at 50° C. in asealed tube for 12 h. The reaction mixture was partitioned betweenaqueous NaHCO₃ (10 mL) and chloroform (10 mL) the organic fraction wasdried on K₂CO₃, filtered and concentrated to give alkynyl macrolide M18as a white solid (18 mg). Data for M18: MS (ESI) m/e 766.7 (M+H)⁺.

Synthesis of Alkynyl Macrolide M15

Telithromycin was selectively N-demethylated and then alkylated with thetosylate of 1-butyn-4-ol as described for azithromycin, erythromycin andclarithromycin above.

Synthesis of 3′-N-Desmethyl Telithromycin 30

To a solution of telithromycin 29 (3.0 g, 3.60 mmol) in anhydrousacetonitrile (70 mL) was added N-iodosuccinimide (NIS) (0.98 g, 4.32mmol) in two portions within 30 min at 0° C. under argon atmosphere. Themixture was allowed to warm to rt and stirred overnight. CH₂Cl₂ (250 mL)and 5% Na₂S₂O₃ (80 mL) were added and the two layers separated. Theorganic layer was extracted with 5% Na₂S₂O₃ (1×80 mL); dilute NH₄Cl(1×80 mL) and dried over Na₂SO₄. Solvent was evaporated and the crudewas purified on silica gel eluting with 0-8% methanolic ammonia (2N NH₃)in CH₂Cl₂ to give compound 30 as white solid (1.95 g, 68%). MS (ESI)MIE; M+H⁺ 798.6.

Scheme 105 Synthesis of Alkynyl Macrolide M15.

Synthesis of 3′-N-(but-3-Ynyl) Telithromycin, M15 Protocol A:

A mixture of amine 30 (0.66 g, 0.83 mmol) and tosylate 11 (0133 g, 1.49mmol) in TH F (15 mL) and Hunig's base (3 mL) was heated at 90° C. for 5days. The solvent was evaporated; the residue was dissolved in 1N HCl(50 mL) and kept stirring at room temperature for about h. CH₂Cl₂ (30mL) was added and the two layers were separated. The aqueous layer wasextracted with CH₂Cl₂ (2×30 mL) and basified with NaOH (1N) to form awhitish-suspension. The suspension was extracted with CH₂Cl₂ (3×30 mL)and the organic layer was dried over Na₂SO₄. Solvent was evaporated andthe crude was purified on silica gel eluting with 0-6% methanolicammonia (2N NH₃) in CH₂Cl₂ to give compound M15 as white solid (0.12 g,17%). MS (ESI) m/e 850.8 (M+H)⁺.

Synthesis of 3′-N-(but-3-Ynyl) Telithromycin, M15 Protocol B:

A mixture of amine 30 (0.66 g, 0.83 mmol), and tosylate 11 (0.40 g, 1.84mmol) in acetonitrile (10 mL) and Hunig's base (0.18 mL, 1.0 mmol) wasmicrowave heated to 90° C. within 10 min and maintained at 90° C. for1.5 h. The reaction was vented within 15 min and solvent was evaporated.The residue was dissolved in 1N HCl (60 mL) and kept stirring at roomtemperature for about 2 h. CH₂Cl₂ (30 mL) was added and the two layerswere separated. The aqueous layer was extracted with CH₂Cl₂ (2×30 mL)and basified with 50% KOH to form a whitish-suspension. The suspensionwas extracted with CH₂Cl₂ (3×30 mL) and the organic layer was dried overNa₂SO₄. The solvent was evaporated and the crude was purified bypreparative TLC (2000 micron plate) eluting with CH₂Cl₂/methanolicammonia (2N NH₃) 12:1 to give compound M15 as white solid (0.19 g, 27%);MS (ESI) n/e 850.8 (M+H)⁺.

Synthesis of Alkynyl Macrolide M19.

Desmethyl telithromycin 30 was treated according to the procedures ofU.S. Pat. No. 6,124,269 to afford the 2-fluoro amine 30a. This was thenalkylated with the tosylate of 1-butyn-4-ol under the conditions formaking M15 to afford the fluorinated alkynyl macrolide M119. Thereactions are outlined in the following scheme.

Synthesis of Alkynyl Macrolides M20, M21, M22, and M23

Alkynyl macrolides M21, M22, and M23 are prepared according to thefollowing reaction scheme from alkynyl macrolide M20. Alkynyl macrolideM20 is in turn made from alkynyl macrolide M14.

Synthesis of Alkynyl Macrolide M20

To a mixture of alkynyl macrolide M14 (1 g, 1.3 mmol) and hydroxylaminehydrochloride (0.4 g, 6.4 mmol) was added methanol (15 mL) andtriethylamine (3.2 mmol). The solution was refluxed for 72 h. Cooled toambient temperature, poured into water (50 mL) and adjusted pH to 11.The resulting solution was extracted with dichloromethane (4×50 mL),dried and concentrated. The crude material was purified by flashchromatography over silica gel to yield M20 (C₂Cl₂:2N NH₃-MeOH=10:1).Yield: 0.6 g (60%).

Synthesis of Alkynyl Macrolide M21

To a solution of alkynyl macrolide M20 (2.00 g, 2.54 mmol) in THF (17mL) at 0° C. was added Et₃N (1.50 mL, 10.67 mmol), followed by additionof acetic anhydride (946 μL, 9.91 mmol), then, DMAP (34 mg, 0.25 mmol).The mixture was stirred at 0° C. for 3 h, then, Et₃N (150 μL, 1.07 mmol)and acetic anhydride (95 μL, 0.99 mmol) were added. The mixture wasstirred for 3 h, then, MeOH (2.0 ml) was added. The reaction mixture wasconcentrated and EtOAc (100 mL) was added, washed with saturated NaHCO₃(30.0 mL), then, brine (30.0 mL), dried with Na₂SO₄, gave 2.28 g ofalkynyl macrolide M21. The residue was used for the next step withoutfurther purification. MS (ESI) m/e 913 (M+H)⁺.

Synthesis of Alkynyl Macrolide M22

To a solution of triacetate alkynyl M21 (913 mg, 100 mmol, crude),2-methylene-1,3-propane-[bis-(tert-butyl)carbonate] (865 mg, 3.00 mmol)and 1,4-bis(diphenylphosphino)-butane (dppb) (305 mg, 0.70 mmol) in THF(10 mL, degassed) was added Pd₂(dba)₃ (92 mg, 0.10 mmol) at roomtemperature. The mixture was refluxed for 12 h, then, the reactionmixture was concentrated and EtOAc (100 mL) was added. Washed withsaturated NaHCO₃ (30 mL), brine (30 mL), dried with Na₂SO₄, The residuewas isolated by silica gel chromatography (CH₂Cl₂ to 2% MeOH in CH₂Cl₂containing 0.2% NH₄OH), gave 340 mg of alkynyl macrolide M22 in 35%yield for two steps. MS (ESI) m/e 966 (M+H)⁺.

Synthesis of Alkynyl Macrolide M23

Alkynyl macrolide M22 (330 mg, 0.34 mmol) in MeOH (6 mL), was refluxedfor 5 days. The residue was isolated by FC (CH₂Cl₂ to 2% MeOH in CH₂Cl₂containing 0.2% NH₄OH), gave 143 mg of alkynyl macrolide M23 in 50%yield. MS (ESI) m/e 839 (M+H)⁺.

Synthesis of Alkynyl Macrolide M24

To a solution of alkynyl macrolide M4 (6.4 g, 9.6 mmol) in pyridine (25mL) was added methanesulfonic anhydride (4.0 g, 22.9 mmol) at 10° C. Thereaction was stirred at ambient temperature for 24 h. The solution wasconcentrated and portioned between ethyl acetate (150 mL) and saturatedNaHCO₃ solution (150 mL). Organic layer was separated and the aqueouslayer was back extracted with ethyl acetate (2×100 mL). The combinedorganic layer was washed with brine (2×150 mL), dried and concentrated.The crude material was purified by flash chromatography over silica gel(50% ethyl acetate in hexane) to give 5.9 g of M24 (83%).

Synthesis of Alkynyl Macrolide M25

To a solution of alkynyl macrolide M24 (5.9 g, 7.9 mmol) in acetone (25mL) was added diazabicycloundecene (DBU) (1.4 mL, 9.5 mmol) at ambienttemperature. After stirring for 48 h, the reaction was diluted withmethylene chloride, washed with water, dried and concentrated in vacuo.The crude material was purified by flash chromatography over silica gel(40% ethyl acetate in hexanes). Yield 3.6 g M25 (70%):

Synthesis of Alkynyl Macrolide M26

To a solution of M25 (3.3 g, 5.0 mmol) in methylene chloride (30 mL) wasadded DBU (1.0 mL, 6.5 mmol) at 0° C. Then was added carbonyldiimidazole(1.0 g, 6.1 mmol) at once. After stirring for 3 h, the reaction wasdiluted with methylene chloride, washed with water, dried andconcentrated in vacuo. The crude material was purified by flashchromatography over silica gel (70% ethyl acetate in hexanes). Yield 3.4g M26 (89%).

Synthesis of Alkynyl Macrolide M27

Alkynyl macrolide M27 is made from alkynyl macrolide M23 by reduction ofthe oxime to the imine followed by acetylation of the compound, which isthen oxidized to give the bridged ketone. The cladinose sugar is thenhydrolyzed by treatment with dilute hydrochloric acid.

Synthesis of Alkynyl Macrolide M28

Alkynyl macrolide M28 is made by refluxing alkynyl macrolide M27 withthe following hydroxyl amine compound in methanol.

Synthesis of Alkynyl Macrolide M2

A mixture of M26 (1.48 g, 2.0 mmol) and hydrazine (0.65 mL, 20 mmol) inacetonitrile (40 mL) and water (6 mL) was heated to 50° C. After 5 h thesolution was concentrated and refluxed with MeOH (100 mL) for 20 h. Thesolution was concentrated and the crude material was purified by flashchromatography over silica gel (60% ethyl acetate in hexane). Yield: 0.8g M2 (60%).

Synthesis of Alkynyl Macrolides MG, M7, and M8

Alkynyl macrolides M6, M7, and M8 are made from M26 (using a procedureanalogous to that for making M2, in which the hydrazine is replaced withmethyl amine, ammonium hydroxide, and ethanol amine respectively.

Synthesis of Azide Compounds

The organic azide compounds used in the synthesis of the compounds ofthe present invention are generally prepared from the iodo compound 2 orthe boronic acid ester compound 3. Typically, the iodo or boronic acidfunctional groups provide a means for preparing a wide range ofcompounds using methods available to one skilled in the art.

The iodo compound 2, is prepared according to the following scheme fromcommercially available(1R,2R)-(−)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. The boronic acidester compound 3 is prepared from the iodo compound 2.

The following reaction scheme illustrates various azide compounds thatcan be made from iodo compound 2. R^(a), R^(b), R^(c), and R^(d)represent various alkyl, substituted alkyl, aryl, and substituted arylgroups.

General Scheme for Synthesis of Various Azide Compounds from IodoCompound 2

Synthesis of Compounds 131, 132, 172, 173, 174, 175, 182, 185, 199, 201,203, and 205

As described above, compounds 131, 132, 172, 173, 174, 175, 182, 185,199, 201, 203, and 205, as well as other similar compounds, are preparedfrom the cycloaddition reaction of the desired alkynyl macrolide andnitro phenyl azide to form a resulting nitro phenyl macrolide compound.This nitro phenyl macrolide is then further converted to an azide group,via reduction to an amine. The azide is a common intermediate which isthen reacted with an appropriately functionalized alkyne in a secondcycloaddition reaction to form the desired compound. Table 4, belowshows the corresponding alkynes used in the preparation of compounds131, 132, 172, 173, 174, 175, 182, 185, 199, 201, 203, and 205. Itshould be noted in the case of compound 132 that the TMS-acetylene isused as the alkyne and the TMS group is then subsequently removed understandard conditions.

TABLE 4 Compound Alkyne 131

132

172

173

174

175

182

185

199

201

203

205

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrugthereof, wherein A is selected from (a) a C₁₋₆ alkyl group, (b) a C₂₋₆alkenyl group, (c) a C₂₋₆ alkynyl group, (d) a C₃₋₁₂ saturated,unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated,unsaturated, or aromatic heterocycle containing one or more nitrogen,oxygen or sulfur atoms, (f) H, (g) —OH, (h) —SH, (i) F, (j) Cl, (k) Br,(l) I, (m) —CF₃, (n) —CN, (o) —N₃, (p) —NO₂, (q) —NR⁶(CR⁶R⁶)_(t)R⁹, (r)—OR⁹, (s) —S(CR⁶R⁶)_(t)R⁹, (t) —S(O)(CR⁶R⁶)_(t)R⁹, (u)—S(O)₂(CR⁶R⁶)_(t)R⁹ (v) —C(O)(CR⁶R⁶)_(t)R⁹, (w) —OC(O)(CR⁶R⁶)_(t)R⁹, (x)—OC(O)O(CR⁶R⁶)_(t)R⁹, (y) —SC(O)(CR⁶R⁶)_(t)R⁹, (z) —C(O)O(CR⁶R⁶)_(t)R⁹,(aa) —NR⁶C(O)(CR⁶R⁶)_(t)R⁹, (bb) —C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (cc)—C(═NR⁶)(CR⁶R⁶)_(t)R⁹, (dd) —C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁹, (ee)—C[═NNR⁶C(O)R⁶](CR⁶R⁶)_(t)R⁹, (ff) —NR⁶C(O)O(CR⁶R⁶)_(t)R⁹, (gg)—OC(O)NR⁶(CR⁶R⁶)_(t)R⁹, (hh) —NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (ii)—NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁹, (jj) —S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁹, (kk) NR⁶R⁶,(ll) NR⁶(CR⁶R⁶)_(t)R⁹, (mm) —SR⁶, (nn) —S(O)R⁶, (oo) —S(O)₂R⁶, (pp)—NR⁶C(O)R⁶, (qq) —Si(R¹³)₃, and (rr) —C(═O)H; wherein (a)-(e) optionallyare substituted with one or more R¹⁴ groups; T is a 14- or 15-memberedmacrolide connected via a macrocyclic ring carbon atom; X is selectedfrom —OR¹⁵ and —SR¹⁵, R¹ and R³ independently are selected from: (a) H,(b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) a C₂₋₆ alkynylgroup, (e) —C(O)R′, (f) —C(O)OR⁵, (g) —C(O)—NR⁴R⁴, (h) —C(S)R⁵, (i)—C(S)OR⁵, (j) —C(O)SR⁵, and (k) —C(S)—NR⁴R⁴; Alternatively, R¹ and R³are taken together with the oxygen to which R¹ is attached, the nitrogento which R³ is attached and the two intervening carbons to form a 5 or 6membered ring, said ring being optionally substituted with one or moreR⁵; R² is hydrogen or —OR¹²; R⁴, at each occurrence, independently isselected from: (a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group,(d) a C₂₋₆ alkynyl group, (e) a C₆₋₁₀ saturated, unsaturated, oraromatic carbocycle, (f) a 3-12 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, (g) —C(O)—C₁₋₆ alkyl, (h) —C(O)—C₂₋₆alkenyl, (i) —C(O)—C₂₋₆ alkynyl, (j) —C(O)—C₆₋₁₀ saturated, unsaturated,or aromatic carbocycle, (k) —C(O)-3-12 membered saturated, unsaturated,or aromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, (l) —C(O)O—C₁₋₆ alkyl, (m) —C(O)O—C₂₋₆alkenyl, (n) —C(O)O—C₂₋₆ alkynyl, (o) —C(O)O—C₆₋₁₀ saturated,unsaturated, or aromatic carbocycle, (p) —C(O)O-3-12 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, and (q) —C(O)NR⁶R⁶, whereinany of (b)-(p) optionally is substituted with one or more R⁵ groups;alternatively, NR⁶R⁶ forms a 3-7 membered saturated, unsaturated oraromatic ring including the nitrogen atom to which the R⁶ groups areattached, wherein said ring is optionally substituted at a positionother than the nitrogen atom to which the R⁶ groups are attached, withone or more substituents selected from O, S(O)_(p), N, and NR⁸; R⁵ isselected from: (a) R⁷, (b) a C₁₋₈ alkyl group, (c) a C₂₋₈ alkenyl group,(d) a C₂₋₈ alkynyl group, (e) a C₃₋₁₂ saturated, unsaturated, oraromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, or two R⁵ groups, when present on the samecarbon atom can be taken together with the carbon atom to which they areattached to form a spiro 3-6 membered carbocyclic ring or heterocyclicring containing one or more heteroatoms selected from nitrogen, oxygen,and sulfur, wherein any of (b)-(f) immediately above optionally issubstituted with one or more R⁷ groups; R⁶, at each occurrence,independently is selected from: (a) H, (b) a C₁₋₆ alkyl group, (c) aC₂₋₆ alkenyl group, (d) a C₂₋₆ alkynyl group, (e) a C₃₋₁₀ saturated,unsaturated, or aromatic carbocycle, and (f) a 3-10 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, wherein any of (b)-(f)optionally is substituted with one or more moieties selected from:  (aa)a carbonyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee) Br, (ff) I,(gg) CN, (hh) NO₂, (ii) —OR⁸, (jj) —S(O)_(p)R⁸, (kk) —C(O)R⁸, (ll)—C(O)OR⁸, (mm) —OC(O)R⁸, (nn) —C(O)NR⁸R⁸, (oo) —OC(O)NR⁸R⁸, (pp)—C(═NR⁸)R⁸, (qq) —C(R⁸)(R⁸)OR⁸, (rr) —C(R⁸)₂OC(O)R⁸, (ss)—C(R⁸)(OR⁸)(CH₂)_(r)NR⁸R⁸, (tt) —NR⁸R⁸, (uu) —NR⁸OR⁸, (vv) —NR⁸C(O)R⁸,(ww) —NR⁸C(O)OR⁸, (xx) —NR⁸C(O)NR⁸R⁸, (yy) —NR⁸S(O)_(p)R⁸, (zz)—C(OR⁸)(OR⁸)R⁸, (ab) —C(R⁸)₂NR⁸R⁸, (ac) ═NR⁸, (ad) —C(S)NR⁸R⁸, (ae)—NR⁸C(S)R⁸, (af) —OC(S)NR⁸R⁸, (ag) —NR⁸C(S)OR⁸, (ah) —NR⁸C(S)NR⁸R⁸, (ai)—SC(O)R⁸, (aj) a C₁₋₈ alkyl group, (ak) a C₂₋₈ alkenyl group, (al) aC₂₋₈ alkynyl group, (am) a C₁₋₈ alkoxy group, (an) a C₁₋₈ alkylthiogroup, (ao) a C₁₋₈ acyl group, (ap) —CF₃, (aq) —SCF₃—, (ar) a C₃₋₁₀saturated, unsaturated, or aromatic carbocycle, and (as) a 3-10 memberedsaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur; alternatively,NR⁶R⁶ forms a 3-10 membered saturated, unsaturated or aromatic ringincluding the nitrogen atom to which the R⁶ groups are attached whereinsaid ring is optionally substituted at a position other than thenitrogen atom to which the R⁶ groups are bonded, with one or moremoieties selected from —O, S(O)_(p), N, and NR⁸; alternatively, CR⁶R⁶forms a carbonyl group; R⁷, at each occurrence, is selected from: (a) H,(b) ═O, (c) ═S, (d) F, (e) Cl, (f) Br, (g) I, (h) —CF₃, (i) —CN, (j)—N₃, (k) —NO₂, (l) —NR⁶(CR⁶R⁶)_(t)R⁹, (m) —OR⁹, (n)—S(O)_(p)C(R⁶R⁶)_(t)R⁹, (o) —C(O)(CR⁶R⁶)_(t)R⁹, (p) —OC(O)(CR⁶R⁶)_(t)R⁹,(q) —SC(O)(CR⁶R⁶)_(t)R⁹, (r) C(O)O(CR⁶R⁶)_(t)R⁹, (s)—NR⁶C(O)(CR⁶R⁶)_(t)R⁹, (t) —C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (u)—C(═NR⁶)(CR⁶R⁶)_(t)R⁹, (v) —C(═NNR⁶R⁶)(CR⁶R⁶)_(t)R⁹, (w)—C(═NNR⁶C(O)R⁶)(CR⁶R⁶)_(t)R⁹, (x) —C(═NOR⁹)(CR⁶R⁶)_(t)R⁹, (y)—NR⁶C(O)O(CR⁶R⁶)_(t)R⁹, (z) —OC(O)NR⁶(CR⁶R⁶)_(t)R⁹, (aa)—NR⁶C(O)NR⁶(CR⁶R⁶)_(t)R⁹, (bb) —NR⁶S(O)_(p)(CR⁶R⁶)_(t)R⁹, (cc)—S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁹, (dd) —NR⁶S(O)_(p)NR⁶(CR⁶R⁶)_(t)R⁹, (ee)—NR⁶R⁶, (ff) NR⁶(CR⁶R⁶), (gg) —OH, (hh) —NR⁶R⁶, (ii) —OCH₃, (jj)—S(O)_(p)R⁶, (kk) —NC(O)R⁶, (ll) a C₁₋₆ alkyl group, (mm) a C₂₋₆ alkenylgroup, (nn) a C₂₋₆ alkynyl group, (oo) —C₃₋₁₀ saturated, unsaturated, oraromatic carbocycle, and (pp) 3-10 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, wherein any of (ll)-(pp) optionally issubstituted with one or more R⁹ groups; alternatively, two R⁷ groupstaken together form —O(CH₂)_(u)O—; R⁸ is selected from: (a) H, (b) aC₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group, (d) a C₂₋₆ alkynyl group,(e) a C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, (f) a 3-10membered saturated, unsaturated, or aromatic heterocycle containing oneor more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)—C(O)—C₁₋₆ alkyl, (h) —C(O)—C₁₋₆ alkenyl, (i) —C(O)—C₁₋₆ alkynyl, (j)—C(O)—C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (k)—C(O)-3-10 membered saturated, unsaturated, or aromatic heterocyclecontaining one or more heteroatoms selected from—nitrogen, oxygen, andsulfur, wherein any of (c)-(k) optionally is substituted with one ormore moieties selected from: (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I,(ff) CN, (gg) NO₂, (hh) OH, (ii) NH₂, (jj) NH(C₁₋₆ alkyl), (kk) N(C₁₋₆alkyl)₂, (ll) a C₁₋₆ alkoxy group, (mm) an aryl group, (nn) asubstituted aryl group, (oo) a heteroaryl group, (pp) a substitutedheteroaryl group, and (qq) a C₁₋₆ alkyl group optionally substitutedwith one or more moieties selected from an aryl group, a substitutedaryl group, a heteroaryl group, a substituted heteroaryl group, F, Cl,Br, I, CN, NO₂, CF₃, SCF₃, and OH; R⁹, at each occurrence, independentlyis selected from: (a) R¹⁰, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenylgroup, (d) a C₂₋₆ alkynyl group, (e) a C₃₋₁₀ saturated, unsaturated, oraromatic carbocycle, and (f) a 3-10 membered saturated, unsaturated, oraromatic heterocycle containing one or more heteroatoms selected fromnitrogen, oxygen, and sulfur, wherein any of (b)-(f) optionally issubstituted with one or more R¹⁰ groups; R¹⁰, at each occurrence,independently is selected from: (a) H, (b) ═O, (c) F, (d) Cl, (e) Br,(f) I, (g) —CF₃, (h) —CN, (i) —NO₂, (j) —NR⁶R⁶, (k) —OR⁶, (l)—S(O)_(p)R⁶, (m) —C(O)R⁶, (n) —C(O)OR⁶, (o) —OC(O)R⁶, (p) NR⁶C(O)R⁶, (q)—C(O)NR⁶R⁶, (r) —C(═NR⁶)R⁶, (s) —NR⁶C(O)NR⁶R⁶, (t) —NR⁶S(O)_(p)R⁶, (u)—S(O)_(p)NR⁶R⁶, (v) —NR⁶S(O)_(p)NR⁶R⁶, (w) a C₁₋₆ alkyl group, (x) aC₂₋₆ alkenyl group, (y) a C₂₋₆ alkynyl group, (z) a C₃₋₁₀ saturated,unsaturated, or aromatic carbocycle, and (aa) a 3-10 membered saturated,unsaturated, or aromatic heterocycle containing one or more heteroatomsselected from nitrogen, oxygen, and sulfur, wherein any of (w)-(aa)optionally is substituted with one or more moieties selected from R⁶, F,Cl, Br, I, CN, NO₂, —OR⁶, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, a C₁₋₆alkoxy group, a C₁₋₆ alkylthio group, and a C₁₋₆ acyl group; R¹¹ at eachoccurrence, independently is selected from: (a) H, (b) F, (c) Cl, (d)Br, (e) I, (f) CN, (g) NO₂, (h) OR⁸, (i) —S(O)_(p)R⁸, (j) —C(O)R⁸, (k)—C(O)OR⁸, (l) —OC(O)R⁸, (m) —C(O)NR⁸R⁸, (n) —OC(O)NR⁸R⁸, (o) —C(═NR⁸)R⁸,(p) —C(R⁸)(R⁸)OR⁸, (q) —C(R⁸)₂OC(O)R⁸, (r) —C(R⁸)(OR⁸)(CH₂)_(r)NR⁸R⁸,(s) —NR⁸R⁸, (t) —NR⁸OR⁸, (u) —NR⁸C(O)R⁸, (v) —NR⁸C(O)OR⁸, (w)—NR⁸C(O)NR⁸R⁸, (x) —NR⁸S(O)_(p)R⁸, (y) —C(OR⁸)(OR⁸)R⁸, (z) —C(R⁸)₂NR⁸R⁸,(aa) —C(S)NR⁸R⁸, (bb) —NR⁸C(S)R⁸, (cc) —OC(S)NR⁸R⁸, (dd) —NR⁸C(S)OR⁸,(ee) —NR⁸C(S)NR⁸R⁸, (ff) —SC(O)R⁸, (gg) —N₃, (hh) —Si(R¹³)₃, (ii) a C₁₋₈alkyl group, (jj) a C₂₋₈ alkenyl group, (kk) a C₂₋₈ alkynyl group, (ll)a C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-10membered saturated, unsaturated, or aromatic heterocycle containing oneor more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein(ii)-(mm) optionally are substituted with one or more R⁵ groups; R¹² isselected from: (a) H, (b) a C₁₋₆ alkyl group, (c) a C₂₋₆ alkenyl group,(d) a C₂₋₆ alkynyl group, (e) —C(O)R⁵, (f) —C(O)OR⁵, (g) —C(O)—NR⁴R⁴,(h) —C(S)R⁵, (i) —C(S)OR⁵, (j) —C(O)SR⁵, (k) —C(S)—NR⁴R⁴, (l) a C₃₋₁₀saturated, unsaturated, or aromatic carbocycle, (m) a 3-10 memberedsaturated, unsaturated, or aromatic heterocycle containing one or moreheteroatoms selected from nitrogen, oxygen, and sulfur, (n) a —(C₁₋₆alkyl)-C₃₋₁₀ saturated, unsaturated, or aromatic carbocycle, and (o) a—(C₁₋₆ alkyl)-3-10 membered saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from—nitrogen,oxygen, and sulfur, wherein (a)-(d) and (l)-(o) optionally aresubstituted with one or more R⁵ groups; R¹³ at each occurrence, isindependently selected from (a) —C₁₋₆ alkyl and (b) —O—(C₁₋₆ alkyl); R¹⁴at each occurrence is independently selected from: (a) H, (b) F, (c) Cl,(d) Br, (e) I, (f) CN, (g) NO₂, (h) OR⁸, (i) —S(O)_(p)R⁸, (j) —C(O)R⁸,(k) —C(O)OR⁸, (l) —OC(O)R⁸, (m) —C(O)NR⁸R⁸, (n) —OC(O)NR⁸R⁸, (o)—C(═NR⁸)R⁸, (p) —C(R⁸)(R⁸)OR⁸, (q) —C(R⁸)₂OC(O)R⁸, (r)—C(R⁸)(OR⁸)(CH₂)NR⁸R⁸, (s) —NR⁸R⁸, (t) —NR⁸OR⁸, (u) —NR⁸C(O)R⁸, (v)—NR⁸C(O)OR⁸, (w) —NR⁸C(O)NR⁸R⁸, (x) —NR S(O)_(p)R⁸, (y) —C(OR⁸)(OR⁸)R⁸,(z) —C(R⁸)₂NR⁸R⁸, (aa) —C(S)NR⁸R⁸, (bb) —NR⁸C(S)R⁸, (cc) —OC(S)NR⁸R⁸,(dd) —NR⁸C(S)OR⁸, (ee) —NR⁸C(S)NR⁸R⁸, (ff) —SC(O)R⁸, (gg) —N₃, (hh)—Si(R¹³)₃, (ii) a C₁₋₈ alkyl group, (jj) a C₂₋₈ alkenyl group, (kk) aC₂₋₈ alkynyl group, (ll) a C₃₋₁₀ saturated, unsaturated, or aromaticcarbocycle, and (mm) a 3-10 membered saturated, unsaturated, or aromaticheterocycle containing one or more heteroatoms selected from nitrogen,oxygen, and sulfur, wherein (ii)-(mm) optionally are substituted withone or more R⁵ groups; alternatively two R¹⁴ groups are taken togetherto form (a) ═O, (b) ═S, (c) ═NR⁸, (e) ═NOR⁸; R¹⁵ is C₁₋₆ alkyl,optionally substituted with from 1 to 13 fluorine atoms; n at eachoccurrence is 0, 1, 2, 3, or 4 p at each occurrence is 0, 1, or 2; r ateach occurrence is 0, 1, or 2; t at each occurrence is 0, 1, or 2; and uat each occurrence is 1, 2, 3, or 4.